Piperidinyl indole and tetrohydropyridinyl indole derivatives and methods of their use

ABSTRACT

3-Piperidin-4-yl-1H-indole and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are disclosed. Methods of using the derivatives and compositions containing the derivatives in the prevention and/or treatment of serotonin disorders, such as depression and anxiety, are also disclosed. Additionally, processes for the preparation of 3-piperidin-4-yl-1H-indole and 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of Ser. No. 10/835,998, filed onApr. 30, 2004, which claims benefit of Provisional Application Ser. No.60/467,345, filed May 2, 2003, the disclosures of which is herebyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to 3-piperidin-4-yl-1H-indole and3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives, processes forpreparing such derivatives, and the use of such derivatives to preventand/or treat a variety of psychological disorders. Preferred compoundsof this invention display activity both as 5-HT_(1A) receptorantagonists and as serotonin uptake inhibitors, and are useful, interalia, in the prevention and/or treatment of serotonin-related disorders.

BACKGROUND OF THE INVENTION

Major depressive disorder affects an estimated 340 million peopleworldwide. Depression is the most frequently diagnosed psychiatricdisorder and, according to the World Health Organization, is the fourthgreatest public health problem. If left untreated, the effects ofdepression can be devastating, robbing people of the energy ormotivation to perform everyday activities and, in some cases, leading tosuicide. Symptoms of the disorder include feelings of sadness oremptiness, lack of interest or pleasure in nearly all activities, andfeelings of worthlessness or inappropriate guilt. In addition to thepersonal costs of depression, the disorder also has been estimated toresult in more than $40 billion in annual costs in the United Statesalone, due to premature death, lost productivity, and absenteeism.

Pharmaceuticals that enhance serotonergic neurotransmission have hadsuccess in preventing and/or treating many psychiatric disorders,including depression and anxiety. The first generation of non-selectiveserotonin-affecting drugs operated through a variety of physiologicalfunctions that endowed them with several side-effect liabilities. Aclass of more recently-developed drugs, selective serotonin reuptakeinhibitors (SSRIs), have had significant success in preventing and/ortreating depression and related illnesses and have become among the mostprescribed drugs since the 1980s. Although they have a favorable sideeffect profile compared to tricyclic antidepressants (TCAs), they havetheir own particular set of side effects due to the non-selectivestimulation of serotonergic sites. They typically have a slow onset ofaction, often taking several weeks to produce their full therapeuticeffect. Furthermore, they have generally been found to be effective inless than two-thirds of patients.

SSRIs are believed to work by blocking the neuronal reuptake ofserotonin, increasing the concentration of serotonin in the synapticspace, thus increasing the activation of postsynaptic serotoninreceptors. Although a single dose of an SSRI can inhibit the neuronalserotonin transporter, and thus would be expected to increase synapticserotonin, long-term treatment is usually required before clinicalimprovement is achieved. It has been suggested that the delay in onsetof antidepressant action of the SSRIs is the result of an increase inserotonin levels in the vicinity of the serotonergic cell bodies. Thisexcess serotonin is believed to activate somatodendritic autoreceptors,i.e., 5-HT_(1A) receptors, reduce cell firing activity, and, in turn,decrease serotonin release in major forebrain areas. This negativefeedback limits the increment of synaptic serotonin that can be inducedby antidepressants acutely. Over time, the somatodendritic autoreceptorsbecome desensitized, allowing the full effect of the SSRIs to beexpressed in the forebrain. This time period has been found tocorrespond to the latency for the onset of antidepressant activity.[Perez, et al., The Lancet, 1997, 349:1594-1597].

In contrast to the SSRIs, a 5-HT_(1A) agonist or partial agonist actsdirectly on postsynaptic serotonin receptors to increase serotonergicneurotransmission during the latency period for the SSRI effect.Accordingly, the 5-HT_(1A) partial agonist buspirone and gepirone[Feiger, A., Psychopharmacol. Bull., 1996, 32: 659-665, Wilcox, C.,Psychopharmacol. Bull., 1996, 32: 335-342], and the 5-HT_(1A) agonistflesinoxan [Grof, P., International Clinical Psychopharmacology, 1993,8: 167-172], have shown efficacy in clinical trials for the treatment ofdepression. Furthermore, such agents are believed to stimulate thesomatodendritic autoreceptors, thus hastening their desensitization anddecreasing the SSRI latency period. Indeed, buspirone augmentation tostandard SSRI therapy has been shown to produce marked clinicalimprovement in patients initially unresponsive to standardantidepressant therapy [Dimitriou, E., J. Clinical Psychopharmacol.,1998, 18: 465-469].

There is still an unfulfilled need for a single agent with a dualmechanism of antidepressant action, i.e., one that not only inhibits orblocks serotonin reuptake (to increase levels of serotonin in thesynapse) but also antagonizes the 5-HT_(1A) receptors (to reduce thelatency period). The present invention is directed to these, as well asother important ends.

SUMMARY OF THE INVENTION

This invention provides novel 3-piperidin-4-yl-1H-indole and3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives. In preferredembodiments, the compounds of this invention inhibit or block serotoninreuptake and/or are antagonists at the 5-HT_(1A) receptor. The compoundsof the invention are thus useful, inter alia, in the prevention and/ortreatment of diseases affected by disorders of the serotonin-affectedneurological systems, including, but not limited to, depression,anxiety, cognitive deficits, such as those resulting form Alzheimer'sdisease and other neurodegenerative disorders, schizophrenia, prostatecancer, and nicotine withdrawal.

In one aspect, the present invention provides 3-piperidin-4-yl-1H-indoleand 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole derivatives havingformula I:

or a prodrug, N-oxide, stereoisomer or a pharmaceutically acceptablesalt thereof, wherein:

A is a heterocycle selected having the following structure:

X is O or S;

R₁ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, fluoro, alkoxy,heteroaryloxy, cycloalkoxy, hydroxy, nitrile, carboxy, alkoxycarbonyl,alkylcarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, fluorinatedalkyl, aryl, aryloxy, alkylaryl, heteroaryl, alkylheteroaryl, NH₂,NHR₁₁, NR₁₁R₁₁, —O-alkyl-NR₁₁R₁₁, or -aryl-O-alkyl-NR₁₁R₁₁;

R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are, independently, hydrogen, alkyl,cycloalkyl, alkenyl, alkynyl, halo, cyano, alkoxy, heteroaryloxy,cycloalkoxy, hydroxy, nitro, nitrile, NH₂, NHR₁₁, NR₁₁R₁₁, CHO,alkylcarbonyl, arylcarbonyl, carboxy, alkoxycarbonyl,alkoxycarbonylalkyl, alkylcarbonyloxy aminocarbonylalkyl,alkylaminocarbonyl, fluorinated alkyl, aryl, aryloxy, alkylaryl,heteroaryl, alkylheteroaryl, —O-alkyl-NR₁₁R₁₁, or -aryl-O-alkyl-NR₁₁R₁₁;

R₁₀ is hydrogen, alkyl, cycloalkyl, alkenyl of 3 to 6 carbon atoms (withthe proviso that the carbon bearing the double bond should not bedirectly connected to N), alkynyl of 3 to 6 carbon atoms (with theproviso that the carbon bearing the triple bond should not be directlyconnected to N), alkoxycarbonyl, alkylcarbonyl, aminocarbonylalkyl,alkylaminocarbonyl, fluorinated alkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, SO₂-aryl, or SO₂-alkyl;

R₂ and R₃, R₃ and R₄, or R₄ and R₅ can each be attached together to forma cycloalkyl or optionally substituted aromatic or hetero aromatic ringcontaining one or two hetero atoms such as N, O, S, S(═O) or SO₂;

R₁₁ is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl (with the proviso that the carbon bearing the double bond is notbonded directly to the heteroatoms such as O, S or N—R₁₁), optionallysubstituted alkynyl (with the proviso that the carbon bearing the triplebond is not bonded directly to the heteroatoms such as O, S or N—R₁₁),optionally substituted aryl, optionally substituted alkylaryl,heteroaryl optionally substituted with R₂, optionally substitutedalkylheteroaryl, SO₂-aryl, SO₂-heteroaryl or SO₂-alkyl;

with the proviso that if two R₁₁ groups are attached to a nitrogen, thenthey can together form a 4- to 7-membered cyclic system having 0 to 2hetero atoms selected from O, S═(O)_(r), where r is an integer from 0 to2, and NR₁₁; and

n is an integer from 1 to 6.

In another aspect, the present invention is directed to compositionscomprising a compound of formula I and one or more pharmaceuticallyacceptable carriers.

In another aspect, the present invention is directed to compositionscomprising a compound of formula I, one or more pharmaceuticallyacceptable carriers, and an SSRI.

Also provided are methods for blocking or inhibiting the neuronalreuptake of serotonin and/or modulating the activity of 5-HT_(1A)receptors through in vitro or in vivo administration of an effectiveamount of a compound of one or more compounds according to theinvention. In this respect, such compounds preferably function as5-HT_(1A) antagonists.

The present invention also provides methods of preventing and/ortreating a patient suspected of suffering from a serotonin-relateddisorder, comprising the step of administering to the patient atherapeutically effective amount of a compound of formula I.

In yet another aspect, the present invention is also directed to methodsof inhibiting the reuptake of serotonin in a patient in need thereof,comprising the step of administering to the patient a therapeuticallyeffective amount of a compound of formula I.

In other aspects, the present invention is also directed to methods ofantagonizing 5-HT_(1A) receptors in a patient in need thereof,comprising the step of administering to the patient a therapeuticallyeffective amount of a compound of formula I.

In a further aspect, the present invention is directed to a method ofantagonizing 5-HT_(1A) receptors and inhibiting the reuptake ofserotonin in a patient in need thereof, comprising the step ofadministering to the patient a therapeutically effective amount of acompound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl”, as used herein, whether used alone or as part ofanother group, refers to a substituted or unsubstituted aliphatichydrocarbon and includes, but is not limited to, straight and branchedchains containing from 1 to 6 carbon atoms, unless explicitly statedotherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyland t-butyl are encompassed by the term “alkyl”.

The term “optionally substituted alkyl”, as used herein, refers to analiphatic hydrocarbon and includes, but is not limited to, straight andbranched chains containing from 1 to 6 carbon atoms, unless explicitlystated otherwise, optionally substituted with 1 or 2 substituents.Suitable substitutions for alkyl, include, but are not limited to, R₂groups, as defined herein above, haloalkyl, haloalkoxy, cyano,alkylcarbonyl, alkoxycarbonylalkyl, and alkylcarbonyloxy.

The carbon number, as used in these definitions herein, refers to carbonbackbone and carbon branching, but does not include carbon atoms ofsubstituents, such as alkoxy substitutions and the like.

The term “alkenyl”, as used herein, whether used alone or as part ofanother group, refers to an aliphatic hydrocarbon chain and includes,but is not limited to, straight and branched chains having 2 to 6 carbonatoms and containing at least one double bond.

The term “optionally substituted alkenyl”, as used herein, refers to analiphatic hydrocarbon and includes, but is not limited to, straight andbranched chains containing from 3 to 6 carbon atoms and containing atleast one double bond, optionally substituted with one or more R₂groups, as defined herein above.

The term “alkynyl”, as used herein, whether used alone or as part ofanother group, refers to an aliphatic hydrocarbon chain and includes,but is not limited to, straight and branched chains having 2 to 6 carbonatoms.

The term “optionally substituted alkynyl”, as used herein, refers to analiphatic hydrocarbon and includes, but is not limited to, straight andbranched chains containing from 3 to 6 carbon atoms and containing atleast one triple bond, optionally substituted with one or more R₂groups, as defined herein above.

The term “cycloalkyl”, as used herein, whether used alone or as part ofanother group, refers to a saturated or unsaturated, substituted orunsubstituted, alicyclic hydrocarbon group having 3 to 10 carbon atoms,including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl. Specifically included within the definitionof “cycloalkyl” are those alicylic hydrocarbon groups that areoptionally substituted.

An optionally substituted cycloalkyl can be substituted with 1 or 2substituents. Suitable substitutions for cycloalkyl include, but are notlimited to, R₂ groups, haloalkyl, haloalkoxy, cyano, alkylcarbonyl,alkoxycarbonylalkyl, alkylcarbonyloxy and hetero atoms such as N, O, S,NR₁₁, or S(O)_(r), where r is 0 to 2. For example, a cycloalkyl withsubstituted with 1 or 2 hetero atoms such as N—R₁₁, O, or S(O)_(r),where r is 0 to 2, includes, but is not limited to, azetidine,pyrrolidine, morpholine, piperidine, piperazine, homopiperazine,tetrahydro, dihydrofuryl, tetrahydro, dihydro pyrane or thiopyran.

The term “aryl”, as used herein, whether used alone or as part ofanother group, refers to a substituted or unsubstituted aromatichydrocarbon ring group containing 6 to 10 carbon atoms, unlessexplicitly stated otherwise, and includes, but is not limited to phenyl,naphthalene, indene and indacene. Specifically included within thedefinition of “aryl” are those aromatic hydrocarbon chains that areoptionally substituted. An optionally substituted aryl refers to asubstituted or unsubstituted aromatic hydrocarbon ring group containing6 to 10 carbon atoms, optionally substituted with 1 to 3 substitutents.Suitable substitutions for aryl, include, but are not limited to, R₂groups, haloalkyl, haloalkoxy, cyano, alkylcarbonyl,alkoxycarbonylalkyl, and alkylcarbonyloxy.

The term “heteroaryl”, as used herein, whether used alone or as part ofanother group, refers to a substituted or unsubstituted aromaticheterocycle ring system (moncyclic or bicyclic) of 4 to 10 carbon atoms,and contains from 1 to 3 heteroatoms selected from S, O or N. The term“heteroaryl” includes, but not limited to, furan, thiophene, pyrrole,imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole,oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, napthyridine,pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine,indole, isoindole, indazole, indolizine, and isobenzofuran. Specificallyincluded with the definition of “heteroaryl” are those aromaticheterocyclic rings that are optionally substituted. An optionallysubstituted heteroaryl may be substituted with 1 to 3 substitutents, andmore preferably 1 to 2 groups. Suitable substitutions for heteroaryl,include, but are not limited to, R₂ groups, haloalkyl, haloalkoxy,cyano, alkylcarbonyl, alkoxycarbonylalkyl, and alkylcarbonyloxy.

The term “alkylaryl”, as used herein, whether used alone or as part ofanother group, refers to the group —R_(a)-R_(b)-, containing 7 to 12carbon atoms, wherein R_(a) is an alkyl group, as defined above, R_(b)is an aryl group, as defined above.

The term “optionally substituted alkylaryl” as used herein, refers to analkylaryl group as defined above, optionally substituted with one ormore R₂ groups.

The term “alkylheteroaryl”, as used herein, whether used alone or aspart of another group, refers to R_(a)-R_(c), containing 7 to 12 carbonatoms, where R_(a) is an alkyl group as defined above, and R_(c) is aheteroaryl group, as defined above.

The term “optionally substituted alkylheteroaryl”, as used herein,refers to an alkylheteroaryl group, as defined above, optionallysubstituted with one or more R₂ groups.

The term “amino”, as used herein, refers to —NH₂, —N(H)R₁₁ or—N(R₁₁)R₁₁.

The term “halo”, as used herein, refers to means chloro, bromo, iodo orfluoro.

The term “alkoxy”, as used herein, whether used alone or as part ofanother group, refers to a substituted or unsubstituted —O—R_(a), whereR_(a) is an alkyl group containing 1 to 6 carbon atoms, as definedabove. Specifically included within the definition of “alkoxy” are thosealkoxy moieties that are optionally substituted. An optionallysubstituted alkoxy may be substituted with 1 or 2 R₂.

The term “alkoxyalkyl”, as used herein, refers to the group—R_(a)-O—R_(a), where R_(a) is an alkyl group, as defined above.

The term “aryloxy”, as used herein, whether used alone or as part ofanother group, refers to the group —O—R_(b)-, where R_(b) is an arylgroup, as defined above.

The term “—O-alkyl-NR₁₁R₁₁”, as used herein, refers to the group—O—R_(a)-N(R₁₁)—R₁₁, where R_(a) is an alkyl group, as defined above.

The term “-aryl-O-alkyl-NR₁₁R₁₁”, as used herein, refers to refers tothe group R_(b)-O—R_(a)-N(R₁₁)—R₁₁, where R_(a) is an alkyl group andR_(b) is an aryl group, as defined above.

The term “heteroaryloxy”, as used herein, refers to the group R_(c)-O—,where R_(c) is a heteroaryl group, as defined above.

The term “cycloalkoxy”, as used herein, refers to a substituted orunsubstituted alicyclic alkoxy group having 3 to 6 carbon atoms.Specifically include with in the definition of “cycloalkoxy” are thosealicyclic alkoxy groups that are optionally substituted. An optionallysubstituted cycloalkoxy may be substituted with 1 or more heteroatomsincluding, but not limited to O, S, and N—R₁₁.

The term “carbonylalkyl”, as used herein, refers to the group—R_(a)-C(═O)—, where R_(a) is an alkyl group containing 1 to 4 carbonatoms, as defined above.

The term “carbonylaryl”, as used herein, refers to the group—R_(b)-C(═O), where R_(b) is an aryl group, as defined above.

The term “alkoxycarbonyl”, as used herein, refers to the group—O—R_(a)-C(═O)—, where R_(a) is an alkyl group containing 1 to 4 carbonatoms, as defined above.

The term “alkoxycarbonylalkyl”, as used herein, refers to the group—O—R_(a)-C(═O)—R_(a)-, where R_(a) is an alkyl group containing 1 to 4carbon atoms, as defined above.

The term “aminocarbonylalkyl”, as used herein, refers to the group—R_(a)C(═O)N(R₁₁)(R₁₁), where R_(a) is an alkyl group containing 1 to 12carbon atoms, as defined above.

The term “alkylaminocarbonyl”, as used herein, refers to the group(R_(a))₂—NH—C(═O), where R_(a) is hydrogen or an alkyl group as definedabove, containing 1 to 12 carbons.

The term “fluorinated alkyl”, as used herein, refers to an alkyl groupcontaining 1 to 4 carbon atoms, as defined above, substituted with 1 ormore fluorine atoms.

The term “alkylcarbonyl”, as used herein, refers to the groupR_(a)-C(═O)—, where R_(a) is an alkyl group containing 1 to 4 carbonatoms, as defined above.

The term “alkylcarbonyloxy”, as used herein, refers to the groupR_(a)-C(═O)O, where R_(a) is an alkyl group containing 1 to 4 carbonatoms, as defined above.

The term “SO₂-aryl”, as used herein, refers to the group S(O₂)—R_(b),where R_(b) is an aryl group, as defined above.

The term “SO₂-heteroaryl”, as used herein, refers to the groupS(O₂)—R_(b), where R_(b) is a heteroaryl group, as defined above.

The term “SO₂-alkyl”, as used herein, refers to the group S(O₂)—R_(a),where R_(a) is an alkyl group, as defined above.

It is understood that the definition of the compounds of formula I, whenR₁, R₂ or R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ contain asymmetriccarbons, encompass all possible stereoisomers and mixtures thereof whichpossess the activity discussed below. In particular, it encompassesracemic modifications and any optical isomers which possess theindicated activity. Optical isomers may be obtained in pure form bystandard separation techniques.

Preferred R₁ groups are hydrogen and alkyl. Particularly preferred arehydrogen, methyl, ethyl, propyl and isopropyl.

Preferred among the above noted R₂ to R₉ groups are hydrogen, halo,alkyl, alkoxy, alkenyl, NR₁₁R₁₁, and cyano. Particularly preferred arehydrogen, chloro, fluoro, methyl ethyl, propenyl, methoxy, and cyano.

Preferred R₁₀ groups are hydrogen, alkyl, aryl and heteroaryl.Particularly preferred are hydrogen and alkyl.

Preferred R₁₁ groups are hydrogen, alkyl, aryl and heteroaryl.Particularly preferred are hydrogen and alkyl.

Preferred aryl groups are phenyl and naphthalene.

Preferred heteroaryls include furan, thiophene, pyrrole, imidazole,oxazole, thiazole, isoxazole, pyrazole, isoxazole, isothiazole,oxadiazole, triazole, thiadiazole, quinolizine, quinoline, andisoquinoline. More preferred heteroaryls include furan, thiophene,imidazole, isoxazole, quinoline, pyridine and pyrazole.

The following compounds are particularly preferred:

-   3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-cyano-1H-indole;-   3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indole;-   3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indole;-   3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-1H-indole;-   3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole;-   3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole;-   3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole;-   3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole;-   3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;-   3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole;-   3-{1-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;    and-   3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl}imidazo[1,2-a]pyridine.

The present invention provides a process for the preparation of acompound of general formula I. These compounds can be prepared bycondensing the appropriately substituted3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole derivatives 13 with theappropriately substituted heterocycles 15 to 17, as illustrated inScheme 1, in polar aprotic solvents such as DMF, THF, DMSO, acetone orethanol in the presence of an acid binding agent, such as an organictertiary base, (such as triethylamine, triethanolamine, DBU, ordiisopropylethylamine); or an alkailine metal carbonate such aspotassium carbonate or sodium carbonate, at 100-150° C. The requiredappropriately substituted 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indolederivatives 13 can be prepared from the commercially available4-piperidone monohydrate hydrochloride 14 and appropriately substitutedindole, as illustrated in Scheme 2.

The heterocycles 15 and 16 may be prepared from commercially availablesubstituted salicyclic acid derivatives (Scheme 3). Appropriatelysubstituted salicyclic derivatives or thiosalicyclic acid derivatives(Scheme 3) are esterified using alcoholic HCl. The compound 21 may bereacted with ethyl bromoacetate acid in refluxing acetone/K₂CO₃ Theresultant diester 22 may be hydrolyzed to the diacid 23. The diacidobtained may be cyclized using anhydrous CH₃COONa/(CH₃CO)₂O to producecompound 24. This may hydrolyzed using 1N HCl to produce compound 25.This compound, on reaction with (triphenylphosphoranylidene)ethylacetateor the appropriately substituted(triphenylphosphoranylidene)ethylacetate derivative, in boiling organicsolvents such as toluene or xylenes, yields compound 26. This can beconverted to 15 or 16 by reduction using LAH and converting it to eithertosylate or iodide using I₂/imidazole. The reaction may be carried outin a temperature range of 80-120° C. at atmospheric pressure for 8-24hours.

(a) MeOH. HCl/Reflux; (b) BrCH₂COOEt/K₂CO₃/Acetone/Reflux; (c)NaOH/EtOH/THF/Reflux; (d) (CH₃CO)₂O/CH₃COONa/CH₃COOH/reflux; (e) 1N.HCl/MeOH/reflux; (f) Ph₃P═CHR₁COOEt/Toluene/Reflux; (g) LAH/THF/0° C.

Compound 17 can be prepared from the commercially availableimidazo[1,2-a]pyridine as outlined in Scheme 4.

(a) PhLi/C₆H₆/Rt; (b) Ph₃P═CHR₁COOEt; (c) LAH/THF; (d)H₂/Pd—C/Pyridine/Tosyl chloride or I₂/Imidazole

Imidazo[1,2-a]pyridine was lithiated using PhLi and the resulting3-lithio derivative was quenched with DMF to yield the 3-formylderivative. This can be converted into 17 by Wittig reaction.

Alternatively compound 25 can be reacted with1-triphenylphosphoranylidene-2-propanone 28 to yield 29, which can bereacted with 3-(1,2,3,6-tetrahydro-4-pyridinyl)1-H-indole derivatives 13using sodium triacetoxyborohydride to give 30 (Scheme 5).

The terms “effective amount”, “therapeutically effective amount” and“effective dosage” as used herein, refer to the amount of a compound offormula I that, when administered to a patient, is effective to at leastpartially ameliorate a condition from which the patient is suspected tosuffer. Such conditions include serotonin disorders, including, but arenot limited to, depression, anxiety, cognitive deficits, such as thoseresulting from Alzheimer's disease and other neurodegenerativedisorders, schizophrenia, prostate cancer, and nicotine withdrawal.

The term “pharmaceutically acceptable salt”, as used herein, refers tosalts derived from organic and inorganic acids such as, for example,lactic, citric, acetic, cinnamic, tartaric, succinic, maleic, malonic,mandelic, malic, oxalic, propionic, fumaric, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic,ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly knownacceptable acids. Where R₁ to R₉ and R₁₁ contain a carboxyl group, saltsof the compounds of this invention may be formed with bases such asalkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg).

The term “patient”, as used herein, refers to a mammal, preferably ahuman.

The terms “administer”, “administering” or “administration”, as usedherein, refer to either directly administering a compound or compositionto a patient, or administering a prodrug derivative or analog of thecompound to the patient, which will form an equivalent amount of theactive compound or substance within the patient's body.

The terms “in combination with”, and “co-administer” refer, in certainembodiments, to the concurrent administration to a patient of SSRIs andthe compounds of formula (I). When administered in combination, eachcomponent may be administered at the same time or sequentially in anyorder at different points in time. Thus, each component may beadministered separately but sufficiently closely in time so as toprovide the desired therapeutic effect.

As used herein, “N-oxide” refers to compounds wherein the basic nitrogenatom of either a heteroaromatic ring or tertiary amine is oxidized togive a quaternary nitrogen bearing a positive formal charge and anattached oxygen atom bearing a negative formal charge.

As used herein, “stereoisomers” refers to compounds that have identicalchemical constitution, but differ as regards the arrangement of theatoms or groups in space.

Compounds of formula I have been found to have affinity for the 5-HTreuptake transporter. They are therefore useful in the prevention and/ortreatment of diseases affected by disorders of the serotonin affectedneurological systems, such as depression and anxiety. The presentinvention accordingly provides pharmaceutical compositions that includethe compound of formula I; and optionally one or morepharmaceutically-acceptable carriers, excipients, or diluents. The term“carrier”, as used herein, shall encompass carriers, excipients anddiluents.

Examples of such carriers are well know to those skilled in the art andare prepared in accordance with acceptable pharmaceutical procedures,such as, for example, those described in Remington's PharmaceuticalSciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company,Easton, Pa. (1985), which is incorporated herein by reference in itsentirety. Pharmaceutical acceptable carriers are those carriers that arecompatible with the other ingredients in the formulation and arebiologically acceptable.

The compounds of formula I can be administered orally or parenterally,neat, or in combination with conventional pharmaceutical carriers.Representative solid carriers include one or more substances that canact as flavoring agents, lubricants, solubilizers, suspending agents,fillers, glidants, compression aids, binders, tablet-disintegratingagents, or encapsulating materials. They are formulated in conventionalmanner, for example, in a manner similar to that use for knownantihypertensive agents, diuretics and β-blocking agents. Oralformulations containing the active compounds of this invention maycomprise any conventionally used oral forms, including tablets,capsules, buccal forms, troches, lozenges and oral liquids, suspensionsor solutions. In powders, the carrier is a finely divided solid that isin admixture with the finely divided active ingredient. In tablets, theactive ingredient is mixed with a carrier having the necessarycompression properties in suitable proportion and compacted in the shapeand size desired. The powders and tablets preferably contain up to 99%of the active ingredient.

Capsules may contain mixtures of the active compound(s) with inertfillers and/or diluents such as the pharmaceutically acceptable starches(e.g. corn, potato or tapioca starch), sugars, artificial sweeteningagents, powdered celluloses, such as crystalline and microcrystallinecelluloses, flours, gelatins, gums, etc.

Useful tablet formulations may be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, microcrystalline cellulose, methyl cellulose,sodium carboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, starches, sugars, low meltingwaxes, and ion exchange resins. Preferred surface modifying agentsinclude nonionic and anionic surface modifying agents. Representativeexamples of surface modifying agents include, but are not limited to,poloxamer 188, benzalkonium chloride, calcium stearate, cetostearlalcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidolsilicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminumsilicate, and triethanolamine. Oral formulations herein may utilizestandard delay or time release formulations to alter the absorption ofthe active compound(s). The oral formulation may also consist ofadministering the active ingredient in water or a fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, and elixirs. The active ingredient can be dissolvedor suspended in a pharmaceutically acceptable oil or fat. The liquidcarrier can obtain other suitable pharmaceutical additives such as, forexample, solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stablizers or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above, e.g. cellulose derivatives,preferably sodium carboxymethyl cellulose solution), alcohols (includingmonohydric alcohols and polyhydric alcohols, e.g. glycols) and theirderivatives, and oils (e.g. fractionated coconut oil and arachis oil).For parenteral administration, the carrier can also be an oily estersuch as ethyl oleate and isopropyl myristate. Sterile liquid carriersare used in sterile liquid form compositions for parenteraladministration. The liquid carrier for pressurized compositions can behalogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions that are sterile solutions orsuspensions can be administered by, for example, intramuscular,intraperitoneal, or subcutaneous injection. Sterile solutions can alsobe administered intravenously. Compositions for oral administration maybe in either liquid or solid form.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention and preferably from 2 to 50 mg. Still further preferredunit dosage forms contain 5 to 25 mg of a compound of the presentinvention. The compounds of the present invention can be administeredorally at a dose range of about 0.01 to 100 mg/kg or preferably at adose range of 0.1 to 10 mg/kg. Such compositions may be administeredfrom 1 to 6 times a day, more usually from 1 to 4 times a day.

When administered for the prevention and/or treatment or inhibition of aparticular disease state or disorder, it is understood that theeffective dosage may vary depending upon the particular compoundutilized, the mode of administration, the condition, and severitythereof, of the condition being treated, as well as the various physicalfactors related to the individual being treated. In therapeuticapplications, compounds of formula I are provided to a patient alreadysuffering from a disease in an amount sufficient to cure, or at leastpartially ameliorate, the symptoms of the disease and its complications.An amount adequate to accomplish this is defined as a “therapeuticallyeffective amount”. The dosage to be used in the prevention and/ortreatment of a specific case must be subjectively determined by theattending physician. The variables involved include the specificcondition and the weight, age, and response pattern of the patient.Effective administration of the compounds of this invention may be givenat an oral dose of from about 0.1 mg/day to about 1,000 mg/day.Preferably, administration will be from about 10 mg/day to about 600mg/day, more preferably from about 50 mg/day to about 600 mg/day, in asingle dose or in two or more divided doses. The projected daily dosagesare expected to vary with route of administration.

Such doses may be administered in any manner useful in directing theactive compounds herein to the patient's bloodstream, including orally,via implants, parentally (including intravenous, intraperitoneal,intraarticularly and subcutaneous injections), rectally, intranasally,topically, ocularly (via eye drops), vaginally, and transdermally.

In some cases it may be desirable to administer the compounds directlyto the airways in the form of an aerosol. For administration byintranasal or intrabrochial inhalation, the compounds of formula I canbe formulated into an aqueous or partially aqueous solution.

The compounds of this invention may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to inhibitthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of formula I can also be administered transdermallythrough the use of a transdermal patch. For the purposes of thisdisclosure, transdermal administrations are understood to include alladministrations across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration may be accomplished through the use of atransdermal patch containing the active compound and a carrier that isinert to the active compound, is non-toxic to the skin, and allowsdelivery of the agent for systemic absorption into the blood stream viathe skin. The carrier may take any number of forms such as creams andointments, pastes, gels, and occlusive devices. The creams and ointmentsmay be viscous liquid or semisolid emulsions of either the oil-in-wateror water-in-oil type. Pastes containing absorptive powders dispersed inpetroleum or hydrophilic petroleum containing the active ingredient mayalso be suitable. A variety of occlusive devices may be used to releasethe active ingredient into the blood stream such as a semi-permeablemembrane covering a reservoir containing the active ingredient with orwithout a carrier, or a matrix containing the active ingredient. Otherocclusive devices are known in the literature.

The compounds of formula I may be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations may bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water soluble suppository bases, such as polyethylene glycolsof various molecular weights, may also be used.

In certain embodiments, the present invention is directed to prodrugs ofcompounds of formula I. The term “prodrug”, as used herein, is intendedto include any covalently bonded carriers which release the activeparent drug, for example, as according to formula I or other formulas orcompounds employed in the methods of the present invention in vivo whensuch prodrug is administered to a mammalian subject. Since prodrugs areknown to enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds employedin the present methods may, if desired, be delivered in prodrug form.Thus, the present invention contemplates methods of delivering prodrugs.Prodrugs of the compounds employed in the present invention, for exampleformula I, may be prepared by modifying functional groups present in thecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound.

Accordingly, prodrugs include, for example, compounds described hereinin which a hydroxy, amino, or carboxy group is bonded to any group that,when the prodrug is administered to a mammalian subject, cleaves to forma free hydroxyl, free amino, or carboxylic acid, respectively. Examplesinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups; and alkyl,carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl,benzyl, and phenethyl esters, and the like.

Various forms of prodrugs are known in the art such as those discussedin, for example, Bundgaard (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed.), “Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38(1992); Bundgaard, Journal of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.), Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975), each of which is incorporatedby reference in its entirety.

The present invention further provides a compound of the invention foruse as an active therapeutic substance. Compounds of formula I are ofparticular use in the prevention and/or treatment of diseases affectedby disorders of serotonin.

The present invention further provides a compound of the invention incombination with a SSRI for use as an active therapeutic substance.

The present invention further provides a method of preventing and/ortreating depression and anxiety in mammals including man, whichcomprises administering to the afflicted mammal an effective amount of acompound or a pharmaceutical composition of the invention.

The present invention further provides a method of preventing and/ortreating depression and anxiety in mammals including man, whichcomprises co-administering to the afflicted mammal an effective amountof a compound or a pharmaceutical composition of the invention incombination with a SSRI.

EXAMPLES Example 1 Preparation of3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 1”)

Step 1: To a stirred solution of methyl salicylate (15.2 g, 0.1 mol) andanhydrous potassium carbonate (50.0 g, excess) in acetone (500 ml),ethyl bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture wasrefluxed for 24 hrs and cooled to room temperature. It was filtered andconcentrated. The oily residue was extracted with chloroform and washedwell with water. The organic layer was dried over anhydrous MgSO₄ andfiltered. It was concentrated and taken to next step without anypurification. White oil; Yield: 22.0 g (92%); 239 (M+H).

Step 2: The methyl-2-(ethoxy-2-oxoethoxy)benzoate obtained from step 1,(11.9 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300 ml) and 5N NaOH(100 ml) was added. The reaction mixture was refluxed for 24 hrs andcooled to room temperature. At the end, it was concentrated to drynessand dissolved in water. The aqueous layer was acidified with con. HCland the separated solid was filtered. It was washed well with water anddried. The product was taken to step without any purification. Whitesolid; Yield: 9.0 g (91%); mp: 125-128° C.; 197 (M+H).

Step 3: The 2-(carboxymethoxy)-benzoic acid compound obtained from step2 (9.8 g, 50 mmol) was dissolved in acetic anhydride (100 ml) andanhydrous sodium acetate (10.0 g, excess) was added. The reactionmixture was heated to 150° C. for 4 hrs. During this time, the reactionmixture turned dark red. The reaction mixture was cooled to roomtemperature and quenched carefully with ice cold water. The red solidobtained was filtered and washed well with water. The red solid obtainedwas suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,benzofuran-3 (2H)-one, precipitated from the reaction mixture. It wasfiltered and washed well with water. It was dried at 40° C. and used forthe next step without further purifications. Yield: 3.5 g (51%); 135(M+H).

Step 4: A mixture of benzofuran-3 (2H)-one (1.34 g, 10 mmol) and(carboxymethylene) triphenylphosphorane (5.22 g, 15 mmol) was refluxedin toluene (100 ml) for 48 hrs. At the end, reaction mixture wasconcentrated and loaded over a silica-gel column. The column was elutedwith hexane (500 ml) and later with 25% ethyl acetate. The product,ethyl(-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield:2.0 g (98%); 205 (M+H).

Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(-1-benzofuran-3-yl)acetate (1.02 g, 5 mmol) in THF (20 mL) wasadded slowly. After the addition, the reaction mixture was stirred atroom temperature for 1 hr and quenched with saturated NH₄Cl solution.The product was extracted with chloroform and washed well with water. Itwas dried over anhydrous MgSO₄; filtered and concentrated. The product,2-(1-benzofuran-3-yl)ethanol, was obtained as a white oil and was pureenough to be taken to the next step without purification. Yield: 800 mg(98%); 163 (M+H).

Step 6: To a stirred solution of 2-(1-benzofuran-3-yl)ethanol (815 mg, 5mmol) in anhydrous pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g,6.0 mmol) was added. The reaction mixture was kept at 0° C. for 48 hrsand quenched with ice cold water. The reaction mixture was extractedwith chloroform, washed well with water and dried over anhydrous MgSO₄.It was filtered and concentrated. The crude product obtained was takento next step without any purification.

A mixture of tosylate (316 mg. 1 mmol) (obtained by the above mentionedprocess) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1mmol) was heated at 120° C. in DMSO in the presence ofN,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, thereaction mixture was quenched with water and extracted with chloroform.The organic layer was washed with water and dried over anhydrous MgSO₄and concentrated to dryness. The dark colored solid was purified bysilica-gel column chromatography by eluting it with 70% ethylacetae:hexane.3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow solid; mp:166° C.; Yield: 150 mg (43%); 343(M+H); ¹H NMR: δ 8.12 (broad s, 1H), 7.92 (d,1H), 7.65-7.2, (m, 8H), 6.3(m, 1H), 3.3 (bs, 2H), 2.98 (m, 2H), 2.8 (m, 4H), 2.6 (m, 2H).

Example 2 Preparation of3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole(“Compound 2”)

3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(342 mg,1 mmol) (obtained from example 1, step 6) in dry THF (50 ml) wasslowly added to a stirred suspension of hexane and washed with 60%sodium hydride (44 mg) at 0° C. After the addition, the reaction mixturewas stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added.The reaction mixture was stirred for 4 hrs and quenched carefully withice cold water. The reaction mixture was extracted with chloroform;washed well with water; dried over anhydrous MgSO₄; filtered andconcentrated. The residue obtained was purified by silica-gel columnchromatography by eluting it with 50% ethyl acetate:hexane. Light greensemi-solid. Yield: 280 mg (78%); 357 (M+H); ¹H NMR: δ7.94 (d, 1H), 7.69(d, 1H), 7.5-7.0 (m, 8H), 6.2 (bs, 1H), 3.8 (s, 3H), 3.49 (bs, 2H), 3.0(m, 2H), 2.85 (m, 4H), 2.6 (bs, 2H).

Example 3 Preparation of3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-1H-indole(“Compound 3”)

3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-1H-indolewas prepared by generally following the procedure outlined in example 1,step 6, starting from the tosylate (316 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-7-ethyl-1H-indole (226 mg, 1 mmol). Theproduct was purified by silica-gel column chromatography by eluting itwith 70% ethyl acetate:hexane. Brown oil; Yield: 210 mg (56%); 371(M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.05 (broad s, 1H, NH); 7.77˜6.90 (m,9H); 6.20 (s,1H); 3.36˜2.60 (m, 12 H); 1.39˜1.35 (t, J=7.6 Hz, 3H).

Example 4 Preparation of3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 4”)

3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example 1,step 6, starting from the tosylate (316 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 70% ethyl acetate:hexane. Brown oil; Yield: 180 mg (50%); 361(M+H); ¹H NMR δ 9.9 (broad s, 1H); 7.93˜7.1 (m, 9H); 6.2 (s, 1H);3.46˜2.48 (m, 10H).

Example 5 Preparation of3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indole(“Compound 5”)

3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indolewas prepared by generally following the procedure outlined in example 1,step 6, starting from the tosylate (316 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-cyano-1H-indole (213 mg, 1 mmol). Theproduct was purified by silica-gel column chromatography by eluting itwith 80% ethyl acetate:hexane. Brown solid; Yield: 239 mg (65%); 369(M+H); ¹H NMR: δ ¹HNMR (400 MHz, CDCl₃): 68.49 (broad, s, 1H, NH);7.69˜6.99 (m, 9H); 6.18˜6.17 (s, 1H); 3.36˜2.46 (m, 10H).

Example 6 Preparation of3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 6”)

3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example 1,step 6, starting from the tosylate (316 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate:hexane. Brown solid; Yield: 60 mg (16%);361(M+H); ¹H NMR: δ (400 MHz, CDCl₃): 610.2 (broad s, 1H, NH); 7.82˜6.93(m, 9H); 6.07 (s,1H); 3.48˜2.50 (m, 10H).

Example 7 Preparation of3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 7”)

Step 1: To a stirred solution of methyl-4-chloro-2-hydroxy-benzoate(18.6 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) inacetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. Thereaction mixture was refluxed for 24 hrs and cooled to room temperature.It was filtered and concentrated. The oily residue was extracted withchloroform and washed well with water. The organic layer was dried overanhydrous MgSO₄ and filtered. It was concentrated and taken to next stepwithout any purification. White oil; Yield: 27.0 g (99%); 273 (M+H).

Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-4-chloro-benzoate obtainedfrom step 1, (13.6 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300 ml)and 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24hrs and cooled to room temperature. At the end it was concentrated todryness and dissolved in water. The aqueous layer was acidified withcon. HCl and the separated solid were filtered. It was washed well withwater and dried. The product was taken to step without any purification.White solid; Yield: 10.0 g (86%); 231 (M+H).

Step 3: The 2-(carboxymethoxy)-4-chloro-benzoic acid compound obtainedfrom step 2 (11.5 g, 50 mmol) was dissolved in acetic anhydride (100 ml)and anhydrous sodium acetate (10.0 g, excess) was added. The reactionmixture was heated to 150° C. for 4 hrs. During this time the reactionmixture turned dark red. The reaction mixture was cooled to roomtemperature and quenched carefully with ice cold water. The red solidobtained was filtered and washed well with water. The red solid obtainedwas suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid,6-chloro-benzofuran-3 (2H)-one, precipitated from the reaction mixture.It was filtered and washed well with water. It was dried at 40° C. andused for the next step without further purifications. Yield: 5.8 g(69%); 169 (M+H).

Step 4: A mixture of 6-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, the reactionmixture was concentrated and loaded over a silica-gel column. The columnwas eluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(6-chloro-1-benzofuran-3-yl)acetate, was obtained as awhite oil. Yield: 2.1 g (87%); 239 (M+H).

Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(6-chloro -1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF(20 mL) was added slowly. After the addition, the reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(6-chloro-1-benzofuran-3-yl)ethanol, was obtained as a whiteoil pure enough to be taken to the next step without purification.Yield: 900 mg (91%); 197 (M+H).

Step 6: To a stirred solution of 2-(6-chloro-1-benzofuran-3-yl)ethanol(980 mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonylchloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at0° C. for 48 hrs and quenched with ice cold water. The reaction mixturewas extracted with chloroform, washed well with water and dried overanhydrous MgSO₄. It was filtered and concentrated. The crude productobtained was taken to next step without any purification.

A mixture of tosylate (350 mg. 1 mmol) (obtained by the above mentionedprocess) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1mmol) was heated at 120° C. in DMSO in the presence ofN,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, thereaction mixture was quenched with water and extracted with chloroform.The organic layer was washed with water and dried over anhydrous MgSO₄and concentrated to dryness. The dark colored solid was purified bysilica-gel column chromatography by eluting it with 70% ethylacetae:hexane.3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow oil; Yield: 220 mg (58%); 377 (M+H); ¹HNMR (400MHz, CDCl₃): δ10.2 (broad s, 1H, NH); 7.82˜7.01 (m, 9H); 6.14 (s, 1H);3.32˜2.49 (m, 10H).

Example 8 Preparation of3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 8”)

3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example 7,step 6, starting from the tosylate (350 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate: hexane. Brown solid; Yield: 189 mg (47%); 395(M+H); ¹HNMR (400 MHz, CDCl₃): δ10.2 (broad s, 1H, NH); 7.90˜6.92 (m,7H); 6.07 (s, 1H); 3.32˜2.49 (m, 11H).

Example 9 Preparation of3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 9”)

3-{1-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example 7,step 6, starting from the tosylate (350 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate:hexane. Brown solid; Yield: 135 mg (34%); 395(M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.5 (broad, s, 1H, NH); 7.81˜6.80 (m,7H); 6.20 (s, 1H); 3.40˜2.60 (m, 11H).

Example 10 Preparation of3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 10”)

Step 1: To a stirred solution of methyl-4-methoxy-2-hydroxy-benzoate(18.2 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) inacetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. Thereaction mixture was refluxed for 24 hrs and cooled to room temperature.It was filtered and concentrated. The oily residue was extracted withchloroform and washed well with water. The organic layer was dried overanhydrous MgSO₄ and filtered. It was concentrated and taken to next stepwithout any purification. White oil; Yield: 24.0 g (89%); 269 (M+H).

Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-4-methoxy-benzoate obtainedfrom the step 1, (13.4 g, 50 mmol ) was dissolved in THF:MeOH (1:1) (300ml) and 5N NaOH (100 ml) was added. The reaction mixture was refluxedfor 24 hrs and cooled to room temperature. At the end it wasconcentrated to dryness and dissolved in water. The aqueous layer wasacidified with con. HCl and the separated solid were filtered. It waswashed well with water and dried. The product was taken to step withoutany purification. White solid; Yield: 8.5 g (75%); 227 (M+H).

Step 3: The 2-(carboxymethoxy)-4-methoxy-benzoic acid compound obtainedfrom the step 2 (11.3 g, 50 mmol) was dissolved in acetic anhydride (100ml) and anhydrous sodium acetate (10.0 g, excess) was added. Thereaction mixture was heated to 150° C. for 4 hrs. During this time thereaction mixture turned dark red. The reaction mixture was cooled toroom temperature and quenched carefully with ice cold water. The redsolid obtained was filtered and washed well with water. The red solidobtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark redsolid, 6-methoxy-benzofuran-3 (2H)-one precipitated from the reactionmixture. It was filtered and washed well with water. It was dried at 40°C. and used for the next step without further purifications. Yield: 4.7g (57%); 165 (M+H).

Step 4: A mixture of 6-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixturewas concentrated and loaded over silica-gel column. The column waseluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(6-methoxy-1-benzofuran-3-yl)acetate was obtained as awhite oil. Yield: 1.8 g (76%); 235 (M+H).

Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(6-methoxy-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF(20 ml) was added slowly. After the addition, the reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(6-methoxy-1-benzofuran-3-yl)ethanol was obtained as a whiteoil and was pure enough to be taken to the next step withoutpurification. Yield: 850 mg (88%); 193 (M+H).

Step 6: To a stirred solution of 2-(6-methoxy-1-benzofuran-3-yl)ethanol(960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g,6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) wereadded at room temperature. The reaction mixture was stirred at roomtemperature for 4 hrs and quenched with water. It was then extractedwith chloroform, washed well with 5% Na₂S₂O₃ solution and the organiclayer was dried over anhydrous MgSO₄. It was filtered and concentrated.The residue was purified by silica-gel column chromatography by elutingit with 30% ethyl acetate: hexane. The product, namely2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brownliquid; Yield: 1.2 g (80%); 302 (M+H).

A mixture of 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1mmol) (obtained by the above mentioned process) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatographybyeluting it with 70% ethyl acetae:hexane.3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow oil; Yield: 180 mg (48%); 373 (M+H); ¹H NMR: δ8.6(d, 1H), 8.25 (bs, 1H), 7.9 (d,1H), 7.6-6.9 (m, 7H), 6.23 (bs, 1H), 3.85(s, 3H), 3.5 (m,2H), 3.0 (m, 2H), 2.8 (m, 4H), 2.65 (m, 2H).

Example 11 Preparation of3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 11”)

3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example10, step 6, starting from the of 2-(6-methoxy-1-benzofuran-3-yl)ethyliodide (301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate: hexane. Brown solid; Yield: 178 mg (45%); 391(M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.50 (broad, s, 1H, NH); 7.81˜6.80 (m,7H); 6.20 (s, 1H); 3.67 (s, 3H); 3.40˜2.60 (m, 11H).

Example 12 Preparation of3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 12”)

3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by following the procedure outlined in example 10, step 6,starting from the of 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301mg, 1 mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole(216 mg, 1 mmol). The product was purified by silica-gel columnchromatography by eluting it with 80% ethyl acetate: hexane. Brownsolid; Yield: 180 mg (46%); 391 (M+H); ¹HNMR (400 MHz, CDCl₃): δ8.50(broad s, 1H, NH); 7.81˜6.80 (m, 7H); 6.2 (s, 1H); 3.67 (s, 3H);3.40˜2.60 (m, 11H).

Example 13 Preparation of3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-cyano-1H-indole(“Compound 13”)

3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example10, step 6, starting from the of 2-(6-methoxy-1-benzofuran-3-yl)ethyliodide (301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate:hexane. Brown solid; mp181° C.; Yield: 250 mg(62%); 398 (M+H); ¹H NMR: δ 9.50 (broad, s, 1H,); 8.2˜6.80 (m, 7H); 6.20(s, 1H); 3.89 (m, 2H); 3.65 m, 2H), 3.55 m,2H), 2.60 (m, 4H).

Example 14 Preparation of3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 14”)

Step 1: To a stirred solution of methyl-5-chloro-2-hydroxy-benzoate(18.6 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) inacetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. Thereaction mixture was refluxed for 24 hrs and cooled to room temperature.It was filtered and concentrated. The oily residue was extracted withchloroform and washed well with water. The organic layer was dried overanhydrous MgSO₄ and filtered. It was concentrated and taken to next stepwithout any purification. White oil; Yield: 22.0 g (80%); 273 (M+H).

Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-5-chloro-benzoate obtainedfrom the step 1, (13.6 g, 50 mmol ) was dissolved in THF:MeOH (1:1) (300ml) and 5N NaOH (100 ml) was added. The reaction mixture was refluxedfor 24 hrs and cooled to room temperature. At the end it wasconcentrated to dryness and dissolved in water. The aqueous layer wasacidified with con. HCl and the separated solid were filtered. It waswashed well with water and dried. The product was taken to step withoutany purification. White solid; Yield: 8.0 g (69%); 231 (M+H).

Step 3: The 2-(carboxymethoxy)-5-chloro-benzoic acid compound obtainedfrom the step 2 (11.5 g, 50 mmol) was dissolved in acetic anhydride (100ml) and anhydrous sodium acetate (10.0 g, excess) was added. Thereaction mixture was heated to 150° C. for 4 hrs. During this time thereaction mixture turned dark red. The reaction mixture was cooled toroom temperature and quenched carefully with ice cold water. The redsolid obtained was filtered and washed well with water. The red solidobtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark redsolid, 5-chloro-benzofuran-3 (2H)-one, precipitated from the reactionmixture. It was filtered and washed well with water. It was dried at 40°C. and used for the next step without further purifications. Yield: 6.2g (73%); 169 (M+H).

Step 4: A mixture of 5-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixturewas concentrated and loaded over a silica-gel column. The column waseluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(5-chloro-1-benzofuran-3-yl)acetate, was obtained as awhite oil. Yield: 1.8 g (75%); 239 (M+H).

Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(5-chloro-1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF(20 ML) was added slowly. After the addition, reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(5-chloro-1-benzofuran-3-yl)ethanol, was obtained as a whiteoil pure enough to be taken to the next step without purification.Yield: 850 mg (86%); 197 (M+H).

Step 6: To a stirred solution of 2-(5-chloro-1-benzofuran-3-yl)ethanol(980 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g,6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) wereadded at room temperature. The reaction mixture was stirred at roomtemperature for 4 hrs and quenched with water. It was extracted withchloroform, washed well with 5% Na₂S₂O₃ solution and the organic layerwas dried over anhydrous MgSO₄. It was filtered and concentrated. Theresidue was purified by silica-gel column chromatography by eluting itwith 30% ethyl acetate:hexane. The product, namely2-(5-chloro-1-benzofuran-3-yl)ethyl iodide, was obtained as brownliquid; Yield: 1.2 g (80%); 306 (M+H).

A mixture of 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (305 mg. 1 mmol)(obtained by the above mentioned process) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatographybyeluting it with 70% ethyl acetae:hexane.3-{1-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as brown solid. mp 54° C.; Yield: 210 mg (55%); 377 (M+H);¹H NMR:δ8.98 (broad, s, 1H,); 7.92˜6.94 (m, 9H); 6.25 (s, 1H); 3.78 (bs,2H); 3.60 (bs, 2H), 3.45 (bs, 2H), 3.25 (bs, 4H).

Example 15 Preparation of3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 15”)

3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example14, step 6, starting from the of 2-(5-chloro-1-benzofuran-3-yl)ethyliodide (306 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate:hexane. Brown solid; Yield: 120 mg (30%); 395(M+H); ¹HNMR (400 MHz, CDCl₃): δ8.57 (broad, s, 1H, NH); 2.56˜6.96 (m,7H); 6.10 (s, 1H); 3.35˜2.50 (m, 11H).

Example 16 Preparation of3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 16”)

3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by following the procedure outlined in example 14, step 6,starting from the of 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg,1 mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216mg, 1 mmol). The product was purified by silica-gel columnchromatography by eluting it with 80% ethyl acetate:hexane. Brown solid;Yield: 180 mg (45%); 395 (M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.74 (broad,s, 1H,); 7.80˜6.70 (m, 7H); 6.20 (s, 1H); 3.50˜2.60 (m, 10H).

Example 17 Preparation of3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 17”)

Step 1: To a stirred solution of 5-fluoro-2-hydroxy-methyl benzoate(17.0 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) inacetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. Thereaction mixture was refluxed for 24 hrs and cooled to room temperature.It was filtered and concentrated. The oily residue was extracted withchloroform and washed well with water. The organic layer was dried overanhydrous MgSO₄ and filtered. It was concentrated and taken to next stepwithout any purification. White oil; Yield: 23.0 g (89%); 257 (M+H).

Step 2: The methyl-5-fluoro-2-(ethoxy-2-oxoethoxy)benzoate obtained fromstep 1, (12.8 g, 50 mmol ) was dissolved in THF:MeOH (1:1) (300 ml) and5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24 hrsand cooled to room temperature. At the end it was concentrated todryness and dissolved in water. The aqueous layer was acidified withcon. HCl and the separated solid were filtered. It was washed well withwater and dried. The product was taken to step without any purification.White solid; Yield: 8.3 g (77%); 215 (M+H).

Step 3: The 2-(carboxymethoxy)-5-fluoro-benzoic acid compound obtainedfrom the step 2 (10.7 g, 50 mmol) was dissolved in acetic anhydride (100ml) and anhydrous sodium acetate (10.0 g, excess) was added. Thereaction mixture was heated to 150° C. for 4 hrs. During this time, thereaction mixture turned dark red. The reaction mixture was cooled toroom temperature and quenched carefully with ice cold water. The redsolid obtained was filtered and washed well with water. The red solidobtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark redsolid, 5-fluoro-benzofuran-3 (2H)-one, precipitated from the reactionmixture. It was filtered and washed well with water. It was dried at 40°C. and used for the next step without further purifications. Yield: 5.8g (76%); 153 (M+H).

Step 4: A mixture of 5-fluoro-benzofuran-3 (2H)-one (1.52 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixturewas concentrated and loaded over a silica-gel column. The column waseluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(5-fluoro-1-benzofuran-3-yl)acetate, was obtained as awhite oil. Yield: 1.8 g (80%); 223 (M+H).

Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(5-fluoro-1-benzofuran-3-yl)acetate (1.11 g, 5 mmol) in THF (20mL) was added slowly. After the addition, the reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(5-fluoro-1-benzofuran-3-yl)ethanol obtained as white oil andwas pure enough to be taken to the next step without purification.Yield: 820 mg (91%); 181 (M+H).

Step 6: To a stirred solution of 2-(5-fluoro-1-benzofuran-3-yl)ethanol(900 mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonylchloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at0° C. for 48 hrs and quenched with ice cold water. The reaction mixturewas extracted with chloroform, washed well with water and dried overanhydrous MgSO₄. It was filtered and concentrated. The crude productobtained was taken to next step without any purification. A mixture oftosylate (334 mg. 1 mmol) (obtained by the above mentioned process) and3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatography byeluting it with 70% ethyl acetate: hexane.3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow solid. mp 158° C.; Yield: 140 mg (38%); 361(M+H); 1H NMR: δ 8.2 (bs, 1H), 7.9 (d,1H), 7.59 (s, 1H), 7.45-7.0 (m,7H), 6.39s, 1H), 3.4 (m, 2H), 3.0 (m, 2H), 2.84 (m, 4H), 2.68 (m, 2H).

Example 18 Preparation of3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indole(“Compound 18”)

3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indolewas prepared by generally following the procedure outlined in example17, step 6, starting from the tosylate (334 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-cyano-1H-indole (223 mg, 1 mmol). Theproduct was purified by silica-gel column chromatography by eluting itwith 80% ethyl acetate: hexane. Yellow solid; mp 259° C. (HCl salt);Yield:120 mg (31%); 386 (M+H).

Example 19 Preparation of3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 19”)

3-{1-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example17, step 6, starting from the tosylate (334 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate: hexane. Dark semi-solid solid; Yield: 180 mg,(47%); 379 (M+H); ¹H NMR: δ9.2 (bs, 1H), 8.8 (d, 1H), 8.3 (s, 1H),8.2-6.8 (m, 6H), 6.2 (m, 1H), 3.9-3.0 (m, 10H).

Example 20 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 20”)

Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, the reactionmixture was concentrated and loaded over silica-gel column. The columnwas eluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(7-methoxy-1-benzofuran-3-yl)acetate was obtained as awhite oil. Yield: 1.9 g (81%); 235 (M+H).

Step 2: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(7-methoxy -1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF(20 mL) was added slowly. After the addition, the reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(7-methoxy-1-benzofuran-3-yl)ethanol obtained as a white oil,was pure enough and taken to the next step without purification. Yield:800 mg (83%); 193 (M+H).

Step 3: To a stirred solution of 2-(7-methoxy-1-benzofuran-3-yl)ethanol(960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g,6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) wereadded at room temperature. The reaction mixture was stirred at roomtemperature for 4 hrs and quenched with water. The reaction mixture wasextracted with chloroform, washed well with 5% Na₂S₂O₃ solution and theorganic layer was dried over anhydrous MgSO₄. It was filtered andconcentrated. The residue was purified by silica-gel columnchromatography by eluting it with 30% ethyl acetate: hexane. Theproduct, namely 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide, wasobtained as brown liquid. Yield: 1.3 g (86%); 302 (M+H).

A mixture of 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1mmol) (obtained by the above mentioned process) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatography byeluting it with 70% ethyl acetae: hexane.3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow solid. mp 156° C.; Yield: 80 mg (21%); 373 (M+H);¹H NMR: δ 8.4 (bs, 1H), 7.9 (d,1H), 7.5 (s, 1H), 7.35-6.80 (m, 7H), 6.2(m,1H), 3.97 (s, 3H), 3.50 (m,2H), 3.19 (m, 2H), 2.93 (m, 4H), 2.67 (m,2H).

Example 21 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 21”)

3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example20, step 3, starting from 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide(301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate: hexane. Brown solid; mp 136° C.; Yield: 120mg (30%); 391 (M+H); ¹H NMR: δ8.25 (bs, 1H), 7.8 (m,1H), 7.4 (s, 1H),7.25 (s,1H), 7.3-6.80 (m, 5H), 6.17 (m,1H), 4.01 (s, 3H), 3.40 (m,2H),3.02 (m, 2H), 2.93 (m, 4H), 2.65 (m, 2H).

Example 22 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 22”)

3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example20, step 3, starting from 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide(301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate: hexane. Brown solid; mp 171° C.; Yield: 60 mg(15%); 391 (M+H); ¹H NMR: δ8.16 (bs, 1H), 7.6-7.5 (m,2H), 7.3-6.75 (m,6H), 6.17 (m,1H), 4.01 (s, 3H), 3.35 (m,2H), 3.19 (m, 2H), 2.91 (m, 4H),2.64 (m, 2H).

Example 23 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indole(“Compound 23”)

3-{1-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-cyano-1H-indolewas prepared by generally following the procedure outlined in example20, step 3, starting from 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide(301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-cyano-1H-indole (223 mg, 1 mmol). Theproduct was purified by silica-gel column chromatography by eluting itwith 80% ethyl acetate: hexane. Brown solid; mp 72° C.; Yield: 50 mg(12%); 398 (M+H); ¹H NMR (DMSO): δ11.2 (bs, 1H), 8.7 (d, 1H), 8.51 (s,1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.79-6.9 (m, 4H), 6.21 (m,1H), 3.92 (s,3H), 3.23 (m,2H), 2.89 9 m, 2H), 2.75 (m, 4H), 2.5 (m, 2H).

Example 24 Preparation of3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 24”)

Step 1: To a stirred solution of methyl-5-methoxy-2-hydroxy-benzoate(18.2 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) inacetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. Thereaction mixture was refluxed for 24 hrs and cooled to room temperature.It was filtered and concentrated. The oily residue was extracted withchloroform and washed well with water. The organic layer was dried overanhydrous MgSO₄ and filtered. It was concentrated and taken to next stepwithout any purification. Yellow oil; Yield: 21.0 g (78%); 269 (M+H).

Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-5-methoxy-benzoate obtainedfrom step 1, (13.4 g, 50 mmol ) was dissolved in THF:MeOH (1:1) (300 ml)and 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24hrs and cooled to room temperature. At the end it was concentrated todryness and dissolved in water. The aqueous layer was acidified withcon. HCl and the separated solid were filtered, washed well with waterand dried. The product was taken to step without any purification. Whitesolid; Yield: 10.2 g (90%); mp 150-153° C.; 227 (M+H).

Step 3: The 2-(carboxymethoxy)-5-methoxy-benzoic acid compound obtainedfrom the step 2 (11.3 g, 50 mmol) was dissolved in acetic anhydride (100ml) and anhydrous sodium acetate (10.0 g, excess) was added. Thereaction mixture was heated to 150° C. for 4 hrs. During this time thereaction mixture turned dark red. The reaction mixture was cooled toroom temperature and quenched carefully with ice cold water. The redsolid obtained was filtered and washed well with water. The red solidobtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark redsolid, 5-methoxy-benzofuran-3 (2H)-one, precipitated from the reactionmixture. It was filtered and washed well with water. It was dried at 40°C. and used for the next step without further purifications. Yield: 6.2g (75%); 165 (M+H).

Step 4: A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, the reactionmixture was concentrated and loaded over silica-gel column. The columnwas eluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(5-methoxy-1-benzofuran-3-yl)acetate, was obtained as awhite oil. Yield: 1.6 g (68%); 235 (M+H).

Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(5-methoxy -1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF(20 mL) was added slowly. After the addition, reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(5-methoxy-1-benzofuran-3-yl)ethanol, obtained as white oil,was pure enough and taken to the next step without purification. Yellowoil; Yield: 900 mg (93%); 193 (M+H).

Step 6: To a stirred solution of 2-(5-methoxy-1-benzofuran-3-yl)ethanol(960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g,6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) wereadded at room temperature. The reaction mixture was stirred at roomtemperature for 4 hrs and quenched with water. It was extracted withchloroform, washed well with 5% Na₂S₂O₃ solution and the organic layerwas dried over anhydrous MgSO₄. It was filtered and concentrated. Theresidue was purified by silica-gel column chromatography by eluting itwith 30% ethyl acetate: hexane. The product, namely2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brownliquid. Yield: 1.1 g (73%); 302 (M+H).

A mixture of 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1mmol) (obtained by the above mentioned process) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatography byeluting it with 70% ethyl acetae: hexane.3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow oil. Yield: 160 mg (43%); 373 (M+H); ¹HNMR (400MHz, CDCl₃): δ8.74 (broad, s, 1H, NH); 7.80˜6.70 (m, 8H); 6.2 (s, 1H);3.90 (s, 3H); 3.50˜2.60 (m, 11H).

Example 25 Preparation of3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 25”)

3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example24, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide(301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate: hexane. Brown solid; Yield: 142 mg (36%); 391(M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.63˜8.61 (dd, J1=1.6 Hz, J2=1.6 Hz,1H); 8.24˜8.19 (s, 1H); 7.60˜6.84 (m, 7H); 6.15˜6.16 (s, 1H); 3.86˜3.82(s, 3H); 3.36˜2.65) (m, 10H).

Example 26 Preparation of3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 26”)

3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example24, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide(301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg, 1 mmol).The product was purified by silica-gel column chromatography by elutingit with 80% ethyl acetate: hexane. Brown solid; Yield: 122 mg (31%); 391(M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.74 (broad, s, 1H, NH); 7.80˜6.70 (m,7H); 6.20 (s, 1H); 3.90 (s, 3H); 3.50˜2.60 (m, 11H).

Example 27 Preparation of3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-1H-indole(“Compound 27”)

3-{1-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-7-ethyl-1H-indolewas prepared by generally following the procedure outlined in example24, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide(301 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-7-ethyl-1H-indole (226 mg, 1 mmol). Theproduct was purified by silica-gel column chromatography by eluting itwith 80% ethyl acetate: hexane. Brown solid; Yield: 156 mg (39%); 401(M+H); ¹HMNR (400 MHz, CDCl₃): δ 8.04 (broad s, 1H, NH); 7.77˜7.75 (d,7.9HZ, 1H); 7.51˜6.88 (m, 7H); 6.23˜6.21 (s, 1H); 3.85 (s, 3H);3.36˜2.65 (m, 12H); 1.25˜1.27 (t, J=7.0 Hz, 3H).

Example 28 Preparation of3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 28”)

Step 1: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(-1-benzothiophene-3-yl)acetate (1.1 g, 5 mmol) in THF (20 mL)was added slowly. After the addition, the reaction mixture was stirredat room temperature for 1 hr and quenched with saturated NH₄Cl solution.The product was extracted with chloroform and washed well with water. Itwas dried over anhydrous MgSO₄; filtered and concentrated. The product,2-(1-benzothiophene-3-yl)ethanol, was obtained as white oil pure enoughand taken to the next step without purification. Yield: 850 mg (95%);179 (M+H).

Step 2: To a stirred solution of 2-(1-benzothiophene-3-yl)ethanol (890mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) wereadded at room temperature. The reaction mixture was stirred at roomtemperature for 4 hrs and quenched with water. It was extracted withchloroform, washed well with 5% Na₂S₂O₃ solution and the organic layerwas dried over anhydrous MgSO₄. It was filtered and concentrated. Theresidue was purified by silica-gel column chromatography by eluting itwith 30% ethyl acetate: hexane. The product, namely2-(1-benzothiophene-3-yl)ethyl iodide, was obtained as brown liquid.Yield: 1.2 g (85%); 285 (M+H).

A mixture of 2-(1-benzothiophene-3-yl)ethyl iodide (284 mg. 1 mmol)(obtained by the above mentioned process) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatography byeluting it with 70% ethyl acetae: hexane.3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow solid. mp 195-198° C.; Yield: 180 mg (50%); 359(M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.12 (broad s, 1H, NH); 7.92˜6.69 (m,10H); 6.25˜6.23 (s, 1H); 3.48˜2.60 (m, 10H).

Example 29 Preparation of3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole(“Compound 29”)

3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(358 mg,1 mmol) (obtained from example 29, step 2) in dry THF (50 ml)was slowly added to a stirred suspension of hexane and washed with 60%sodium hydride (44 mg) at 0° C. After the addition, the reaction mixturewas stirred for 330 min and allyl bromide (183 mg, 1.5 mmol) was added.The reaction mixture was stirred for 4 hrs and quenched carefully withice cold water. The reaction mixture was extracted with chloroform;washed well with water; dried over anhydrous MgSO₄; filtered andconcentrated. The residue obtained was purified by silica-gel columnchromatography by eluting it with 50% ethyl acetate: hexane. Yellowsemi-solid. Yield: 195 mg (48%); 399 (M+H); ¹HNMR (400 MHz, CDCl₃): δ7.99˜7.87 (m, 3H); 7.42˜6.99 (m, 6H); 6.22˜6.21 (s, 1H); 5.22˜5.21 (d,J=1.3 Hz, 2H); 5.20 5.19 (d, J=1.3 Hz, 2H); 4.71˜4.65 (d, 1.6 Hz, 2H);3.49˜2.67 (m, 10H).

Example 30 Preparation of3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole(“Compound 30”)

3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(358 mg,1 mmol) (obtained from example 29, step 2) in dry THF (50 ml)was slowly added to a stirred suspension of hexane and washed with 60%sodium hydride (44 mg) at 0° C. After the addition, the reaction mixturewas stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added.The reaction mixture was stirred for 4 hrs and quenched carefully withice cold water. The reaction mixture was extracted with chloroform;washed well with water; dried over anhydrous MgSO₄; filtered andconcentrated. The residue obtained was purified by silica-gel columnchromatography by eluting it with 50% ethyl acetate: hexane. Light greensemi-solid. Yield: 98 mg (26%); 373 (M+H); ¹HNMR (400 MHz, CDCl₃):8.08˜7.82 (m, 3H); 7.40˜6.90 (m, 7H); 6.21˜6.19 (s, 1H); 3.80 (s, 3H);3.48˜2.60 (m, 10H).

Example 31 Preparation of3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 31”)

Step 1: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(5-chloro-1-benzothiophene-3-yl)acetate (1.27 g, 5 mmol) in THF(20 mL) was added slowly. After the addition, the reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(5-chloro-1-benzothiophene-3-yl)ethanol, was obtained aswhite oil, was pure enough and taken to the next step withoutpurification. Yield: 920 mg (86%); 213 (M+H).

Step 2: To a stirred solution of2-(5-chloro-1-benzothiophene-3-yl)ethanol (1060 mg, 5 mmol) in anhydrousTHF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. Thereaction mixture was stirred at room temperature for 4 hrs and quenchedwith water. It was extracted with chloroform, washed well with 5%Na₂S₂O₃ solution and the organic layer was dried over anhydrous MgSO₄.It was filtered and concentrated. The residue was purified by silica-gelcolumn chromatography by eluting it with 30% ethyl acetate: hexane. Theproduct, namely 2-(5-chloro-1-benzothiophene-3-yl)ethyl iodide, wasobtained as brown liquid; Yield: 1.1 g (69%); 319 (M+H).

A mixture of 2-(5-chloro-1-benzothiophene-3-yl)ethyl iodide (318 mg. 1mmol) (obtained by the above mentioned process) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatography byeluting it with 70% ethyl acetate: hexane.3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow oil; Yield: 115 mg (29%); 393 (M+H); ¹H -NMR: δ8.10(1H, s, NH), 7.91(1H, d, J=8 Hz), 7.77(2H, m), 7.25(6H, m), 6.24(1H,s), 3.37(2H, d, J=3 Hz), 3.18(2H, t, J=7.7 Hz), 2.87(4H, m), 2.68(2H,s).

Example 32 Preparation of3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole(“Compound 32”)

3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(392 mg,1 mmol) (obtained from example 32, step 2) in dry THF (50 ml)was slowly added to a stirred suspension of hexane and was washed with60% sodium hydride (44 mg) at 0° C. After the addition, the reactionmixture was stirred for 30 min and allyl bromide (183 mg, 1.5 mmol) wasadded. The reaction mixture was stirred for 4 hrs and quenched carefullywith ice cold water. The reaction mixture was extracted with chloroform;washed well with water; dried over anhydrous MgSO₄; filtered andconcentrated. The residue obtained was purified by silica-gel columnchromatography by eluting it with 50% ethyl acetate: hexane. Yellowsemi-solid. Yield: 156 mg (36%); 432 (M+H); ¹H NMR: δ 7.90(1H, s, NH),7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 5.99(1H, m), 5.13(2H, m), 4.71(2H,m), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).

Example 33 Preparation of3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole(“Compound 33”)

3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(392 mg,1 mmol) (obtained from example 32, step 2) in dry THF (50 ml)was slowly added to a stirred suspension of hexane washed 60% sodiumhydride (44 mg) at 0° C. After the addition, the reaction mixture wasstirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. Thereaction mixture was stirred for 4 hrs and quenched carefully with icecold water. The reaction mixture was extracted with chloroform; washedwell with water; dried over anhydrous MgSO₄; filtered and concentrated.The residue obtained was purified by silica-gel column chromatography byeluting it with 50% ethyl acetate: hexane. Brown semi-solid. Yield: 150mg (36%); 407 (M+H); ¹H NMR: δ 7.91(1H, m), 7.78(3H,m), 7.26(6H, m),6.21(1H, s), 3.77(3H,s), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H,s).

Example 34 Preparation of3-{1-(2-Naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole(“Compound 34”)

Step 1: To a stirred solution of 1-hydroxy-naphthalene-2-carboxylic acidmethyl ester (20.2 g, 0.1 mol) and anhydrous potassium carbonate (50.0g, excess) in acetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) wasadded. The reaction mixture was refluxed for 24 hrs and cooled to roomtemperature. It was filtered and concentrated. The oily residue wasextracted with chloroform and washed well with water. The organic layerwas dried over anhydrous MgSO₄ and filtered. It was concentrated andtaken to next step without any purification. White oil; Yield: 22.0 g(92%); 239 (M+H).

Step 2: The 1-methoxycarbonylmethoxy-naphthalene-2-carboxylic acidmethyl ester obtained from the step 1, (13.7 g, 50 mmol) was dissolvedin THF:MeOH (1:1) (300 ml) and 5N NaOH (100 ml) was added. The reactionmixture was refluxed for 24 hrs and cooled to room temperature. At theend it was concentrated to dryness and dissolved in water. The aqueouslayer was acidified with con. HCl and the separated solid was filtered.It was washed well with water and dried. The product,1-carboxymethoxy-naphthalene-2-carboxylic acid was taken to step without any purification. White solid; Yield: 10.0 g (81%); 247 (M+H).

Step 3: The 1-carboxymethoxy-naphthalene-2-carboxylic acid compoundobtained from step 2 (12.3 g, 50 mmol) was dissolved in acetic anhydride(100 ml) and anhydrous sodium acetate (10.0 g, excess) was added. Thereaction mixture was heated to 150° C. for 4 hrs. During this time thereaction mixture turned dark red. The reaction mixture was cooled toroom temperature and quenched carefully with ice cold water. The redsolid obtained was filtered and washed well with water. The red solidobtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark redsolid, naphtho[1,2-b]furan-3 (2H)-one, precipitated from the reactionmixture. It was filtered and washed well with water. It was dried at 40°C. and used for the next step without further purifications. Yield: 4.5g (48%); 185 (M+H).

Step 4: A mixture of naphtho[1,2-b]furan-3 (2H)-one (1.85 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixturewas concentrated and loaded over a silica-gel column. The column waseluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, naphtho[1,2-b]furan-3-yl-acetic acid ethyl ester was obtainedas a white oil. Yield: 2.2 g (86%); 255 (M+H).

Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., naphtho[1,2-b]furan-3-yl-acetic acid ethyl ester (1.27 g, 5 mmol) inTHF (20 mL) was added slowly. After the addition, reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-naphtho[1,2-b]furan-3-yl ethanol, was obtained as white oil,was pure enough and taken to the next step without purification. Yield:900 mg (84%); 213 (M+H).

Step 6: To a stirred solution of 2-naphtho[1,2-b]furan-3-yl ethanol(1.06 g, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g,6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) wereadded at room temperature. The reaction mixture was stirred at roomtemperature for 4 hrs and quenched with water. It was extracted withchloroform, washed well with 5% Na₂S₂O₃ solution and the organic layerwas dried over anhydrous MgSO₄. It was filtered and concentrated. Theresidue was purified by silica-gel column chromatography by eluting itwith 30% ethyl acetate: hexane. The product, namely3-(2-iodo-ethyl)-naphtho[1,2-b]furan, was obtained as brown liquid.Yield: 1.4 g (87%); 322 (M+H).

A mixture of 3-(2-iodo-ethyl)-naphtho[1,2-b]furan (321mg. 1 mmol)(obtained by the above mentioned process) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1 mmol) was heatedat 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml,excess) for 24 hrs. At the end, the reaction mixture was quenched withwater and extracted with chloroform. The organic layer was washed withwater and dried over anhydrous MgSO₄ and concentrated to dryness. Thedark colored solid was purified by silica-gel column chromatography byeluting it with 70% ethyl acetate: hexane.3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow solid. Yield: 120 mg (30%); 393 (M+H).

Step 7:3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole (197mg, 0.5 mmol) obtained from step 6, was hydrogenated over 10% Pd/C inethanol at 40 psi pressure. At the end, reaction mixture was filteredthrough a pad of celite and concentrated. The product obtained waspurified by silica-gel column chromatography by eluting it with 70%ethyl acetate: hexane.3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole wasisolated as yellow solid; Yield: 160 mg (81%); 395 (M+H); ¹H NMR: δ 8.30(1H, d, J=8 Hz), 7.99 (1H, s, NH), 7.94(1H, d, J=8 Hz), 7.67(4H, m),7.58(1H, t, J=8 Hz), 7.48(1H, t, J=8 Hz), 7.38(1H, d, J=8 Hz), 7.20(1H,t, J=8 Hz), 7.13(1H, t, J=8 Hz), 7.0(1H, s), 3.21(2H, d, J=12 Hz),3.04(1H, m), 2.90(1H, m), 2.84(2H, m), 2.29(2H, m), 2.13(2H, d, J=12Hz), 1.90(2H, m, J=12 Hz).

Example 35 Preparation of3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 35”)

Step 1: A mixture of benzofuran-3 (2H)-one (1.34 g, 10 mmol) andethyl-2-(triphenylphosphoranylidene)propionate (5.436 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, the reactionmixture was concentrated and loaded over silica-gel column. The columnwas eluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(-1-benzofuran-3-yl)propanoate was obtained as a whiteoil. Yield: 1.6 g (67%); 219 (M+H).

Step 2: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(-1-benzofuran-3-yl)propanoate (1.09 g, 5 mmol) in THF (20 mL)was added slowly. After the addition, the reaction mixture was stirredat room temperature for 1 hr and quenched with saturated NH₄Cl solution.The product was extracted with chloroform and washed well with water. Itwas dried over anhydrous MgSO₄; filtered and concentrated. The product,2-(1-benzofuran-3-yl)-1-propanol, was obtained as white oil, was pureenough and taken to the next step without purification. Yield: 700 mg(79%); 177 (M+H).

Step 3: To a stirred solution of 2-(1-benzofuran-3-yl)-1-propanol (880mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonyl chloride(1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0° C. for48 hrs and quenched with ice cold water. The reaction mixture wasextracted with chloroform, washed well with water and dried overanhydrous MgSO₄. It was filtered and concentrated. The crude productobtained was taken to next step without any purification.

A mixture of tosylate (331 mg. 1 mmol) (obtained by the above mentionedprocess) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1mmol) was heated at 120° C. in DMSO in the presence ofN,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, thereaction mixture was quenched with water and extracted with chloroform.The organic layer was washed with water and dried over anhydrous MgSO₄and concentrated to dryness. The dark colored solid was purified bysilica-gel column chromatography by eluting it with 70% ethyl acetate:hexane.3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow oil; Yield: 110 mg (30%); 357 (M+H); ¹HNMR (400MHz, CDCl₃): δ 8.16˜8.11 (s, 1H, NH); 7.91˜6.99 (m, 10H); 6.21˜6.10 (s,1H); 3.70˜2.60, 9H); 1.46˜1.44 (d, J=7.0 Hz, 3H).

Example 36 Preparation of3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 36”)

3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example35, step 3, starting from the tosylate (example 36, step 3) (331 mg, 1mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg,1 mmol). The product was purified by silica-gel column chromatography byeluting it with 80% ethyl acetate: hexane. Brown oil; Yield: 148 mg(39%); 375 (M+H); ¹HNMR (400 MHz, CDCl₃): δ 8.03 (broad s, 1H, NH);7.79˜6.89 (m, 9H); 6.17˜6.15 (s, 1H); 3.35˜2.60 (m, 9H); 1.46˜1.44 (d,J=7.0 Hz, 3H).

Example 37 Preparation of3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 37”)

3-{1-[2-(1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example35, step 3, starting from the tosylate (example 36, step 3) (331 mg, 1mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg,1 mmol). The product was purified by silica-gel column chromatography byeluting it with 80% ethyl acetate: hexane. Brown oil; Yield: 160 mg(42%); 375 (M+H); ¹HNMR (400 MHz, CDCl₃): δ8.56˜8.46 (broad s, 1H, NH);7.65˜6.94 (m, 9H); 6.10˜6.09 (s, 1H); 3.48˜2.58 (m, 9H); 1.46˜1.44 (d,7.0 Hz, 3H).

Example 38 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 38”)

Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol)and ethyl-2-(triphenylphosphoranylidene)propionate (5.436 g, 15 mmol)was refluxed in toluene (100 ml) for 48 hrs. At the end, the reactionmixture was concentrated and loaded over a silica-gel column. The columnwas eluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(7-methoxy-1-benzofuran-3-yl)propanoate, was obtained as awhite oil. Yield: 1.9 g (76%); 249 (M+H).

Step 2: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(7-methoxy-1-benzofuran-3-yl)propanoate (1.24 g, 5 mmol) in THF(20 mL) was added slowly. After the addition, the reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct, 2-(7-methoxy-1-benzofuran-3-yl)-1-propanol, was obtained aswhite oil, was pure enough and taken to the next step withoutpurification. Yield: 900 mg (87%); 207 (M+H).

Step 3: To a stirred solution of2-(7-methoxy-1-benzofuran-3-yl)-1-propanol (1.03 g, 5 mmol) in anhydrouspyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) wasadded. The reaction mixture was kept at 0° C. for 48 hrs and quenchedwith ice cold water. The reaction mixture was extracted with chloroform,washed well with water and dried over anhydrous MgSO₄. It was filteredand concentrated. The crude product obtained was taken to next stepwithout any purification.

A mixture of tosylate (360 mg. 1 mmol) (obtained by the above mentionedprocess) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198 mg, 1mmol) was heated at 120° C. in DMSO in the presence ofN,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, thereaction mixture was quenched with water and extracted with chloroform.The organic layer was washed with water and dried over anhydrous MgSO₄and concentrated to dryness. The dark colored solid was purified bysilica-gel column chromatography by eluting it with 70% ethyl acetate:hexane.3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indolewas isolated as yellow solid. mp 156° C.; Yield: 160 mg (41%); 387(M+H); ¹H NMR (DMSO): δ11.2 (bs, 1H), 7.8 9s, 1H), 7.3-6.8 (m, 8H), 6.1(bs, 1H), 3.9 (s, 3H), 3.3-2.6 (m, 9H), 1.4 (d, 3H).

Example 39 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indole(“Compound 39”)

3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-5-fluoro-1H-indolewas prepared by generally following the procedure outlined in example38, step 3, starting from the tosylate (example 39, step 3) (360 mg, 1mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-5-fluoro-1H-indole (216 mg,1 mmol). The product was purified by silica-gel column chromatography byeluting it with 80% ethyl acetate: hexane. Brown solid; Yield: 120 mg(29%); 405 (M+H); ¹1HNMR (400 MHz, CDCl₃): δ8.13 (broad, 1H, NH);7.90˜6.20 (m, 7H); 6.10 (s, 1H); 3.96 (s, 3H); 3.30˜2.60(m, 10H);1.20˜1.21 (d, J=7.2 Hz, 3H).

Example 40 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 40”)

3{1-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example38, step 3, starting from the tosylate (example 39, step 3) (360 mg, 1mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216 mg,1 mmol). The product was purified by silica-gel column chromatography byeluting it with 80% ethyl acetate: hexane. Brown solid; Yield: 180 mg(44%); 405 (M+H); ¹HNMR (400MHZ, CDCl₃): δ 8.13 (broad, s, 1H, NH);7.90˜6.30 (m, 7H), 6.10 (s, 1H); 3.96 (s, 3H); 3.30˜2.60 (m, 10H);120˜1.23 (d, J=7.2 Hz, 3H).

Example 41 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 41”)

Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol)and 1-triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, the reactionmixture was concentrated and loaded over a silica-gel column. The columnwas eluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, 1-(7-methoxy-1-benzofuran-3-yl)acetone, was obtained as a redoil. Yield: 1.4 g (68%); 205 (M+H).

Step 2: To a stirred mixture of 1-(7-methoxy-1-benzofuran-3-yl)acetone(204 mg, 1 mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198.0mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml),sodium triacetoxyborohydride (422 mg, 2 mmol) was added at roomtemperature. The reaction mixture was stirred at room temperature for 72hrs. At the end, the reaction mixture was neutralized with 10% NaHCO₃and extracted with chloroform. The organic layer was dried overanhydrous MgSO₄; filtered and concentrated. The product obtained waspurified by silica-gel column chromatography by eluting it with 80%ethyl acetate: hexane. Brown solid; Yield: 150 mg (38%); 387 (M+H);¹HNMR (400 MHz, CDCl₃): δ8.31 (broad, s, 1H, NH); 7.92˜6.88 (m, 8H);6.25 (s, 1H); 3.85 (s, 3H); 3.50˜2.60 (m, 10H); 1.03˜1.05 (d, J=8.0 Hz,3H).

Example 42 Preparation of3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole(“Compound 42”)

3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indolewas prepared by generally following the procedure outlined in example41, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone(204 mg, 1 mmol) and 3(1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216.0 mg, 1 mmol)in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodiumtriacetoxyborohydride (422 mg, 2 mmol). The product was purified bysilica-gel column chromatography by eluting it with 80% ethyl acetate:hexane. Brown solid; Yield: 60 mg (14%); 405 (M+H); ¹HNMR (400 MHz,CDCl₃): δ 8.31 (broad, s, 1H, NH); 7.92˜6.88 (m, 7H); 6.25 (s, 1H); 3.85(s, 3H), 3.50˜2.60 (m, 10H); 1.03˜1.05 (d, J=8.0 Hz, 3H).

Example 43 Preparation of3-{1-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole(“Compound 43”)

Step 1: A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol)and 1-triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixturewas concentrated and loaded over silica-gel column. The column waseluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, 1-(5-methoxy-1-benzofuran-3-yl)acetone was obtained as a redoil. Yield: 1.1 g (53%); 205 (M+H).

Step 2: To a stirred mixture of 1-(5-methoxy-1-benzofuran-3-yl)acetone(204 mg, 1 mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (198.0mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml),sodium triacetoxyborohydride (422 mg, 2 mmol) was added at roomtemperature. The reaction mixture was stirred at room temperature for 72hrs. At the end, the reaction mixture was neutralized with 10% NaHCO₃and extracted with chloroform. The organic layer was dried overanhydrous MgSO₄; filtered and concentrated. The product obtained waspurified by silica-gel column chromatography by eluting it with 80%ethyl acetate: hexane. Brown solid; Yield: 120 mg (31%); 387 (M+H);¹HNMR(400 MHz, CDCl₃):δ 8.31 (broad, s, 1H, NH); 7.92˜6.88 (m, 8H); 6.25(s, 1H); 3.85 (s, 3H); 3.50˜2.60 (m, 10H); 1.03˜1.05 (d, J=8.0 Hz, 3H).

Example 44 Preparation of3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl}imidazo[1,2-a]pyridine(“Compound 44”)

Step 1: To a stirred solution of imidazo[1,2-a]pyridine (5.9 g, 50 mmol)in dry diethyl ether (100 ml) at room temperature, phenyllithium (1.8 Msolution in cyclohexane:ether, 27.7 ml, 50 mmol) was slowly added. Thereaction mixture was stirred at room temperature for 1 hr and cooled to-78° C. and tert-butyl-4-oxo-1-piperidine carboxylate (9.9 g, 50 mml) inTHF (50 ml) was added slowly. Reaction mixture was stirred at roomtemperature for 4 hrs and quenched with ice cold water and extractedwith chloroform; washed well with water and dried over anhydrous MgSO₄,filtered and concentrated. The product,4-hydroxy-4-imidazo[1,2-a]pyridin-3-yl-piperidine-1-carboxylic acidtert-butyl ester, was purified by silica-gel column chromatography byeluting it with ethyl acetate. Yield: 6.g (37%); Brown oil; 320 (M+H).

Step 2: To a stirred solution of4-hydroxy-4-imidazo[1,2-a]pyridin-3-yl-piperidine-1-carboxylic acidtert-butyl ester (2.0 g 6.26 mmol) in CH₂Cl₂ (100 ml) trifluoro aceticacid (10 ml) was added at room temperature. The reaction mixture wasstirred at room temperature for 24 hrs. At the end, the reaction mixturewas basified with methanolic ammonia and concentrated to dryness. Theresidue was directly chromatographed over silica-gel column and elutedwith methanol:10% methanolic ammonia. The product,4-imidazo[1,2-a]pyridin-3-yl-piperidin-4-ol was obtained as yellow oil;Yield; 620 mg (48%); 218 (M+H).

Step 3: To a stirred solution of methyl-5-chloro-2-hydroxy-benzoate(18.6 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) inacetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. Thereaction mixture was refluxed for 24 hrs and cooled to room temperature.It was filtered and concentrated. The oily residue was extracted withchloroform and washed well with water. The organic layer was dried overanhydrous MgSO₄ and filtered. It was concentrated and taken to next stepwithout any purification. White oil; Yield: 20.0 g (73%); 273 (M+H).

Step 4: The methyl-2-(ethoxy-2-oxoethoxy)-5-chloro-benzoate obtainedfrom step 3, (13.6 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300 ml)and 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24hrs and cooled to room temperature. At the end it was concentrated todryness and dissolved in water. The aqueous layer was acidified withcon. HCl and the separated solid were filtered. It was washed well withwater and dried. The product was taken to step without any purification.White solid; Yield: 8.0 g (69%); 231 (M+H).

Step 5: The 2-(carboxymethoxy)-5-chloro-benzoic acid compound obtainedfrom step 4 (11.5 g, 50 mmol) was dissolved in acetic anhydride (100 ml)and anhydrous sodium acetate (10.0 g, excess) was added. The reactionmixture was heated to 150° C. for 4 hrs. During this time the reactionmixture turned dark red. The reaction mixture was cooled to roomtemperature and quenched carefully with ice cold water. The red solidobtained was filtered and washed well with water. The red solid obtainedwas suspended in 1 N hydrochloric acid and refluxed for 2 hrs. A darkred solid, 5-chloro-benzofuran-3 (2H)-one, precipitated from thereaction mixture. It was filtered and washed well with water. It wasdried at 40° C. and used for the next step without furtherpurifications. Yield: 3.8 g (45%); 169 (M+H).

Step 6: A mixture of 5-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol)and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) wasrefluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixturewas concentrated and loaded over silica-gel column. The column waseluted with hexane (500 ml) and later with 25% ethyl acetate. Theproduct, ethyl(5-chloro-1-benzofuran-3-yl)acetate was obtained as awhite oil. Yield: 1.8 g (75%); 239 (M+H).

Step 7: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0°C., ethyl(5-chloro -1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF(20 mL) was added slowly. After the addition, reaction mixture wasstirred at room temperature for 1 hr and quenched with saturated NH₄Clsolution. The product was extracted with chloroform and washed well withwater. It was dried over anhydrous MgSO₄; filtered and concentrated. Theproduct 2-(5-chloro-1-benzofuran-3-yl)ethanol, was obtained as whiteoil, was pure enough and taken to the next step without purification.Yield: 850 mg (86%); 197 (M+H).

Step 8: To a stirred solution of 2-(5-chloro-1-benzofuran-3-yl)ethanol(980 mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonylchloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at0° C. for 48 hrs and quenched with ice cold water. The reaction mixturewas extracted with chloroform, washed well with water and dried overanhydrous MgSO₄. It was filtered and concentrated. The crude productobtained was taken to next step without any purification.

A mixture of tosylate (350 mg. 1 mmol) (obtained by the above mentionedprocess) and 4-imidazo[1,2-a]pyridine-3-yl-piperidin-4-ol (217 mg, 1mmol) (obtained from step 2) was heated at 120° C. in DMSO in thepresence of N,N-diisopropylethylamine (5 ml, excess) for 72 hrs. At theend, the reaction mixture was quenched with water and extracted withchloroform. The organic layer was washed with water and dried overanhydrous MgSO₄ and concentrated to dryness. The dark colored solid waspurified by silica-gel column chromatography by eluting it with 100%ethyl acetate.3-{1-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}imidazo[1,2-a]pyridinewas isolated as yellow oil. Yield: 110 mg (29%); 378 (M+H); ¹HNMR (400MHz, CDCl₃): 8.46˜8.28 (m, 1H); 7.94˜6.03 (m, 8H); 6.02 (s, 1H);3.41˜2.58 (m, 10H).

Example 45

Testing of Compounds

The 5-HT transporter affinity of the compounds of this invention wasestablished in accordance with standard pharmaceutically accepted testprocedures with representative compounds as follows:

Rat Brain ³H-Paroxetine Binding Assay (RB 5HT Transporter)

This assay was used to determine a compound's affinity of the 5-HTtransporter. A protocol similar to that used by Cheetham et. al.(Neuropharmacol., 1993, 32: 737) was used. Briefly, frontal corticalmembranes prepared from male S.D. rats were incubated with ³H-parxetine(0.1 nM) for 60 min. at 25° C. All tubes also contained either vehicle,test compound (one to eight concentrations), or a saturatingconcentration of fluoxetine (10 μM) to define specific binding. Allreactions are terminated by the addition of ice cold Tris bufferfollowed by rapid filtration using a Tom Tech filtration device toseparate bound from free ³H-paroxetine. Bound radioactivity wasquantitated using a Wallac 1205 Beta Plate® counter. Nonlinearregression analysis was used to determine IC₅₀ values which wereconverted to K_(i) values using the method of Cheng and Prusoff(Biochem. Pharmacol., 1973, 22: 3099).$K_{i} = \frac{{IC}_{50}}{{Radioligand}\quad{{concentration}/\left( {1 + {KD}} \right)}}$Inhibition of ³H-5-HT Uptake By Cells Possessing the Human 5-HTTransporter (HC 5HT Transporter)

A human carcinoma cell line (Jar cells) possessing low endogenous levelsof the 5-HT-transporter are seeded into 96 well plates and treated withstaurosporine at least 18 hrs prior to assay. [Staurosporine greatlyincreases the expression of the 5-HT-transporter.] On the day of assay,vehicle, excess of fluoxetine, or test compound is added to variouswells on the plate. All wells then receive ³H-5-HT and are incubated at37° C. for 5 min. The wells are then washed with ice cold 50 mM Tris HCl(pH 7.4) buffer and aspirated to remove free ³H-5-HT. 25 μl of 0.25 MNaOH is then added to each well to lyse the cells and 75 μlscintillation cocktail (Microscint™ 20) added prior to quantitation on aPackard TopCount machine. Tubes with vehicle represent total possibleuptake, radioactivity counted in tubes with fluoxetine representnonspecific binding/uptake and is subtracted from the total possibleuptake to give total possible specific uptake. This nonspecific binding(usual low in number) is then subtracted from the counts obtained inwells with various test compounds (or different concentrations of testdrug) to give specific uptake in the presence of drug. Specific uptakeis then expressed as a % of control values and is analyzed usingnonlinear regression analysis (Prizm) to determine IC₅₀ values. If thecompound is active at inhibiting 5-HT uptake, its counts will be closeto that obtained with fluoxetine.

High affinity for the serotonin 5-HT_(1A) receptor was established bytesting the claimed compound's ability to displace [³H] 8-OH-DPAT(dipropylaminotetralin) from the 5-HT_(1A) serotonin receptor followinga modification of the procedure of Hall et al. (J. Neurochem., 1985, 44:1685) which utilizes CHO cells stably transfected with human 5-HT_(1A)receptors. The 5-HT_(1A) affinities for the compounds of the inventionare reported below as K_(i)s.

Antagonist activity at 5-HT_(1A) receptors was established by using a³⁵S-GTPγS binding assay similar to that used by Lazareno and Birdsall(Br. J. Pharmacol., 1993, 109: 1120), in which the test compound'sability to affect the binding of ³⁵S-GTPγS to membranes containingcloned human 5-HT_(1A) receptors was determined. Agonists produce anincrease in binding whereas antagonists produce no increase but ratherreverse the effects of the standard agonist 8-OH-DPAT. The testcompound's maximum inhibitory effect is represented as the I_(max),while its potency is defined by the IC₅₀.

Results from these two assays are presented below in Table I. TABLE IRB-5HT HC-5HT 5-HT_(1A) Transporter Transporter Example K_(i)(nM)K_(i)(nM) K_(i)(nM) Compound 1 36.11 1.33 210.00 Compound 2 18.34 6.00Not tested Compound 3 Not tested 156.00 328.00 Compound 4 563.35 2.5548.1 Compound 5 42%* 90.00 15.40 Compound 6 248.05 14.00 282.00 Compound7 49%* 12.00 126.00 Compound 8 30%* 300.00 600.00 Compound 9 45%* 3.5454.20 Compound 10 56.33 3.36 44.60 Compound 11 66.35 3.63 66.80 Compound12 302.70 1.20 36.30 Compound 13 12.67 3.36 34.10 Compound 14 29%* 14.0059.70 Compound 15 46%* 15.00 152.00 Compound 16 60%* 3.00 49.10 Compound17 190.45 3.14 49.30 Compound 18 41.47 4.13 25.30 Compound 19 300.359.25 245.50 Compound 20 8.46 2.85 190.00 Compound 21 10.99 0.76 20.60Compound 22 10.09 3.17 493.00 Compound 23 5.14 3.24 44.40 Compound 2423%* 11.00 28.90 Compound 25 44%* 54.00 216.00 Compound 26  8%* 5.5024.60 Compound 27 39%* 41.00 251.00 Compound 28 67.90 6.25 11.05Compound 29 243.30 104.00 1120.00 Compound 30 53.15 13.00 421.00Compound 31 29%* 172.00 2900.00 Compound 32 34%* 132.00 NT Compound 3345%* 39.00 NT Compound 34 48%* 62.00 276.00 Compound 35 28%* 16.00130.00 Compound 36 11%* 4.43 42.00 Compound 37 20%* 21.00 152.00Compound 38 29.17 3.98 62.80 Compound 39 48%* 13.00 178.00 Compound 4048%* 1.97 37.60 Compound 41 11.48 8.93 68.80 Compound 42 69.39 3.7448.70 Compound 43 34%* 12.00 144.00 Compound 44 44%* 97.00 63.80*% inhibition at 1 μM.

Hence, the compounds of this invention not only inhibit or blockserotonin reuptake (thereby increasing levels of serotonin in thesynapse) but also antagonize the 5-HT_(1A) receptors (thereby reducingthe latency period). The compounds of the invention would thus be usefulin the prevention and/or treatment of diseases affected by disorders ofthe serotonin affected neurological systems, including depression,anxiety, cognitive deficits, such as those resulting from Alzheimer'sdisease and other neurodegenerative disorders, schizophrenia, prostatecancer, and nicotine withdrawal, by administration orally, parenterally,or by aspiration to a patient in need thereof.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges specific embodiments thereinare intended to be included.

The disclosures of each patent, patent application, and publicationcited or described in this document are herby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. The compound of formula I:

or a N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,wherein: A is a heterocycle having the formula:

X is O or S; R₁ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,fluoro, alkoxy, heteroaryloxy, cycloalkoxy, hydroxy, nitrile, carboxy,alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl,fluorinated alkyl, aryl, aryloxy, alkylaryl, heteroaryl,alkylheteroaryl, NH₂, NHR₁₁, NR₁₁R₁₁, —O-alkyl-NR₁₁R₁₁, or-aryl-O-alkyl-NR₁₁R₁₁; R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are,independently, hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, halo,cyano, alkoxy, heteroaryloxy, cycloalkoxy, hydroxy, nitro, nitrile, NH₂,NHR₁₁, NR₁₁R₁₁, CHO, alkylcarbonyl, arylcarbonyl, carboxy,alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy aminocarbonyl,alkylaminocarbonyl, fluorinated alkyl, aryl, aryloxy, alkylaryl,heteroaryl, alkylheteroaryl, —O-alkyl-NR₁₁R₁₁, or -aryl-O-alkyl-NR₁₁R₁₁;R₁₀ is hydrogen, alkyl, cycloalkyl, alkenyl of 3 to 6 carbon atoms (withthe proviso that the carbon bearing the double bond should not bedirectly connected to N), alkynyl of 3 to 6 carbon atoms (with theproviso that the carbon bearing the triple bond should not be directlyconnected to N), alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,alkylaminocarbonyl, fluorinated alkyl, aryl, alkylaryl, heteroaryl,alkylheteroaryl, SO₂-aryl, SO₂-heteroaryl or SO₂-alkyl; R₂ and R₃, R₃and R₄, or R₄ and R₅ can be attached together to form a cycloalkyl oroptionally substituted aromatic or hetero aromatic ring containing oneor two hetero atoms such as N, O, S, S═O or SO₂; R₁₁ is hydrogen,optionally substituted alkyl, optionally substituted alkenyl (with theproviso that the carbon bearing the double bond is not bonded directlyto the heteroatoms such as O, S or N—R₁₁), optionally substitutedalkynyl (with the proviso that the carbon bearing the triple bond is notbonded directly to the heteroatoms such as O, S or N—R₁₁), optionallysubstituted aryl, optionally substituted alkylaryl, heteroaryloptionally substituted with R₂, optionally substituted alkylheteroaryl,SO₂-aryl, SO₂-heteroaryl or SO₂-alkyl; with the proviso that if two R₁₁groups are attached to nitrogen, then they can together form a 4 to 7membered cyclic system having 0 to 2 hetero atoms selected from O,S═(O)_(r), r is an integer from 0 to 2, and NR₁₁; and n is an integerfrom 1 to
 6. 2. A compound according to claim 1, wherein said R₁ ishydrogen or alkyl.
 3. A compound according to claim 1, wherein R₂, R₃,R₄, R₅, R₆, R₇, R₈, and R₉ are independently hydrogen, halo, alkyl,alkoxy, alkenyl, NR₁₁R₁₁, or cyano.
 4. A compound according to claim 1,wherein said R₁₀ is hydrogen, alkyl, aryl or heteroaryl.
 5. A compoundaccording to claim 1, wherein said R₁₁ is hydrogen, alkyl, aryl orheteroaryl.
 6. A compound according to claim 1, wherein said compoundis:3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole;3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole;3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-(2-propenyl)-1H-indole;3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-methyl-1H-indole;or 3-{1-(2-naphtho[1,2-b]furan-3-yl-ethyl)-piperidin-4-yl]-1H-indole. 7.A composition, comprising the compound of claim 1 and one or morepharmaceutically acceptable carriers.
 8. A method of preventing and/ortreating a patient suspected of suffering from a serotonin-relateddisorder, comprising the step of administering to the patient atherapeutically effective amount a compound of claim
 1. 9. A methodaccording to claim 8, wherein said serotonin-related disorder isdepression, anxiety, cognitive deficits, schizophrenia, prostate cancer,or nicotine withdrawal.
 10. A method according to claim 8, wherein saidserotonin-related disorder is depression.
 11. A method according toclaim 8, wherein said serotonin-related disorder is anxiety.
 12. Amethod of antagonizing 5-HT_(1A) receptors in a patient in need thereof,comprising the step of administering to the patient a therapeuticallyeffective amount of a compound of claim
 1. 13. A method of inhibitingthe reuptake of serotonin in a patient in need thereof, comprising thestep of administering to the patient a therapeutically effective amountof a compound of claim
 1. 14. A method of antagonizing 5-HT_(1A)receptors and inhibiting the reuptake of serotonin in a patient in needthereof, comprising the step of: administering to the patient atherapeutically effective amount of a compound of claim 1.